COMPOUNDS FOR USE AS APPETITE SUPPRESSANT

FIELD OF THE INVENTION

The present invention relates to new compounds, in particular compounds capable of ameliorating the metabolic syndrome, and their uses, especially for the treatment of diseases and disorders.

BACKGROUND OF THE INVENTION

Today millions of people are obese. At the individual level, obesity reduces life expectancy by 3-4 years causing complications such as type 2 diabetes, psychosocial disorders, cancers among many others. Therapeutic options for weight loss exist in the form of lifestyle therapy, weight-lowering drugs and/or bariatric surgeries depending on the disease severity and complications. Unfortunately, all offer a poor benefit/risk ratio to reduce obesity and to prevent the onset of obesity-associated complications.

Anti-obesity or weight loss drugs are pharmacological agents that reduce or control weight. These drugs may alter either appetite, absorption of calories and/or energy expenditure.

In the United States, orlistat (Xenical) is currently approved by the FDA for long-term use. It reduces intestinal fat absorption by inhibiting pancreatic lipase. However, severe liver damage has been reported as side effects. Rimonabant (Acomplia), a second drug, works via a specific blockade of the endocannabinoid system. It had been approved in Europe for the treatment of obesity but has not received approval in the United States or Canada due to safety concerns. The European Medicines Agency in October 2008 recommended the suspension of the sale of rimonabant as the risks seem to be greater than the benefits. Sibutramine (Meridia), which acts in the brain to inhibit deactivation of the neurotransmitters, thereby decreasing appetite, was withdrawn from the United States and Canadian markets in October 2010 due to cardiovascular concerns. Lorcaserin, marketed under the brand name Belviq, is a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating a type of serotonin receptor known as the 5-HT2C receptor in a region of the brain called the hypothalamus, which is known to control appetite. However, it was removed from the market in the United States in 2020 due to its increased risk of cancer. Qsymia (phentermine-topiramate) was approved by the FDA in 2012 for the chronic treatment of obesity. Combining the appetite suppressant amphetamine-like properties of phentermine to topiramate, an anticonvulsive drug bearing weight loss potential, provides modest results on obesity treatments. However, common adverse effects such as insomnia, constipation, dizziness, paresthesia, dysgeusia and dry mouth are associated to its use and, even more cardiovascular risks and possible kidney alterations have been reported. Contrave is the combination of naltrexone, an opioid antagonist, with bupropion, originally prescribed as an antidepressant, and was recently approved by FDA and EMA for the treatment of obesity. Common side effects are nausea, constipation, headache, dizziness, vomiting, insomnia, dry mouth and diarrhea. Its use is contraindicated in case of hypertension, seizure and alimentary disorder antecedents. Liraglutide is a GLP-1 receptor mono-agonist. It was approved by FDA and EMA for the treatment of obesity. Liraglutide treatment is frequently associated with gastrointestinal side effects, nausea, diarrhea, constipation and vomiting.

Because of potential side effects, and limited evidence of benefits in weight reduction, anti-obesity drugs are only prescribed for obesity where it is hoped that the benefits of the treatment outweigh its risks.

Therefore, there is a strong need of an appetite suppressor with a high efficacy and a good safety profile.

SUMMARY OF THE INVENTION

The present invention relates to compounds capable of reducing food intake and their uses for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. In addition, the present invention relates to new compounds, a pharmaceutical or veterinary composition comprising a new compound according to the disclosure and their uses as a drug.

More particularly, the present invention relates to a compound of formula (A) for use as appetite suppressant, in particular for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain, wherein the compound has the formula (A) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof

Cy-Y-L-B-A (A) wherein

Cy is a ring selected from the group consisting of a) with

- Ri is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a cyano, a hydroxy, an ethynyl (- CECH), an amino, and/or a halogen; - Xi, X2 and X3 are independently N or CRa with Ra being independently selected from the group consisting of H, a C1-C3 alkyl optionally substituted by at least one halogen, and a halogen; with X4, X ₅ and Xg being independently N or CH; R2 being a Ci-Cg alkyl, linear, branched or cyclic, optionally substituted by a halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; R3, R4, Rs and Rg being independently selected from the group consisting of H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, and a C1-C3 alkoxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy; c) with X ₇ , Xg, and Xg being independently N or CRb and at least one of X ₇ , Xg, and Xg is N, and X10 being

CRb, with Rb being H or a C1-C3 alkyl optionally substituted by a halogen, a hydroxy, a C1-C3 alkyloxy, or a NR'R' with R' being H or a C1-C3 alkyl; R ₇ being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen or a C1-C3 alkyloxy; d) with Xu being a heteroatom, preferably S, O or NRc with Rc being H or a Ci-Cg alkyl optionally substituted by at least one halogen, more preferably S, X12 being N or CH and X13 being CH or N; Rg being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen or a C1-C3 alkyloxy; - Y is present or absent and is selected from the group consisting of -S-, -NRd-, -O-, sulfinyl, sulfonyl, - C(O)-NRd-, and -C(O)-, with Rd being H or C1-C3 alkyl optionally substituted by at least one halogen;

- L is present or absent and is selected from the group consisting of a linear C1-C4 alkylenyl, optionally comprising a double or triple bound, and optionally substituted by a C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl, a heterocycloalkyl, an aryl and a heteroaryl, in particular a 5- or 6-membered cycloalkyl or heterocycloalkyl, especially a 5- or 6-membered heterocycloalkyl,

- B is present or absent and is selected from the group consisting of -NR _e -, -C(O)-NR _e -, -NR _e -C(O)-, - C(O)-, sulfinyl, sulfonyl, S(O)-NR _e -, -S(O2)-NR _e -, -NR _e -S(O)- and -NRe-SfCh)-, with R _e being H or a C1-C3 alkyl optionally substituted by at least one halogen,

- A is a ring selected from the group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and a 5-10- membered heteroaryl, said ring being optionally substituted by substitution(s) selected from the group consisting of a halogen, a cyano, a hydroxy, an ethynyl (-C=CH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, said ring, Ci- Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In a particular embodiment, the present invention relates to a compound for use as mentioned above, wherein the compound has a formula (B) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof wherein

- Ri is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a cyano, a hydroxy, an ethynyl (- CECH), an amino, and/or a halogen;

- Xi, X2 and X3 are independently N or CRa with Ra being independently selected from the group consisting of H, C1-C3 alkyl optionally substituted by at least one halogen and a halogen;

- Y is present or absent and is selected from the group consisting of S, -NH-, -O-, sulfinyl, and sulfonyl,

- L is present or absent and is selected from the group consisting of a linear C1-C2 alkylenyl, optionally comprising a double or triple bound, and optionally substituted by a C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl and a heterocycloalkyl, preferably a 5- or 6-membered cycloalkyl or heterocycloalkyl,

- B is present or absent and is selected from the group consisting of -NR _e -, -NR _e -C(O)-, -C(O)-, -S(O)-, - S(O ₂ )-, -C(O)-NR _e -, -S(O)-NR _e -, -S(O ₂ )-NR _e -, -NR _e -S(O)-and -NR _e -S(O ₂ )-, with R _e being H or a C1-C3 alkyl optionally substituted by at least one halogen,

- A is a ring selected from the group consisting of a phenyl, a 5-10-membered heteroaryl and a 5-10- membered heterocycloalkyl, said ring being optionally substituted by the substitution(s) being selected from the group consisting of halogen, cyano, hydroxy, ethynyl (-CECH), amino group, nitro, amido, guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci- Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

The present application also relates to a new compound having the formula (B) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof wherein - Ri is selected from the group consisting of aryl, 6-10-membered heteroaryl, cycloalkyl, heterocycloalkyl, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a cyano, a hydroxy, an ethynyl (-CECH), an amino, and/or a halogen;

- Xi, X2 and X3 are independently N or CRa with Ra being independently selected from the group consisting of H, C1-C3 alkyl optionally substituted by at least one halogen and a halogen, with at least two among Xi, X2 and X3 being N; preferably Xi is CH and X2 and X3 are N;

- Y is present or absent and is selected from the group consisting of S, NH, O, sulfinyl, and sulfonyl,

- L is present or absent and is selected from the group consisting of a linear C1-C2 alkylenyl, optionally comprising a double or triple bound and optionally substituted by a C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl and a heterocycloalkyl, in particular a 5- or 6-membered cycloalkyl or heterocycloalkyl,

- B is present or absent and is selected from the group consisting of -NR _e -, -NR _e -C(O)-, -C(O)-, -S(O)-, - S(O ₂ )-, -C(O)-NR _e -, -S(O)-NR _e -, -S(O ₂ )-NR _e -, -NR _e -S(O)-and -NR _e -S(O ₂ )-, with R _e being H or a C1-C3 alkyl optionally substituted by at least one halogen,

- A is a ring selected from the group consisting of a phenyl, a 5-10-membered heteroaryl and a 5-10- membered heterocycloalkyl, said ring being optionally substituted by the substitution(s) being selected from the group consisting of halogen, cyano, hydroxy, ethynyl (-CECH), amino group, nitro, amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci- Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH- C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen; and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, this substitution is not in a vicinal position of the ring with respect to the connecting bound of A to the rest of the compound.

More particularly, the compound of formula (B) has -Y-L-B- selected in the group consisting of -NH- C(O)-NH-, -NH-S(O)-NH-, -NH-S(O ₂ )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O ₂ )-NH-, -S-CH ₂ - C(O)-NH-, -S-CH ₂ -S(O)-NH-, -S-CH ₂ -S(O ₂ )-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)- NH-, -O-CH ₂ -S(O)-NH-, -O-CH ₂ -S(O ₂ )-NH-, -NH-CH ₂ -C(O)-NH-, -NH-CH ₂ -S(O)-NH-, -NH-CH ₂ -S(O ₂ )-NH-, -

O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -O-(CH ₂ ) ₂ -NH-S(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -O-(CH ₂ ) ₂ -NH-

S(O ₂ )-, -O-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -S-(CH ₂ ) ₂ -NH-C(O)-, -S-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -S-(CH ₂ ) ₂ -NH-S(O)-, -S-

(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -S-(CH ₂ ) ₂ -NH-S(O ₂ )-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -NH-(CH ₂ ) ₂ -NH-C(O)-, -NH-(CH ₂ ) ₂ -

N(CH ₃ )-C(O)-, -NH-(CH ₂ ) ₂ -NH-S(O)-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -NH-(CH ₂ ) ₂ -NH-S(O ₂ )-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-

S(O ₂ )-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-

CH(CH ₃ )-CH ₂ -NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O)-, -O-CH ₂ -

CH(CH ₃ )-NH-S(O)-, -O-CH(CH ₃ )-CH ₂ -NH-S(O)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-S(O ₂ )-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-

NH-S(O ₂ )-, -O-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -O-CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -S-CH ₂ -

CH(CH ₂ -OCH ₃ )-NH-C(O)-, -S-CH ₂ -CH(CH ₃ )-NH-C(O)-, -S-CH(CH ₃ )-CH ₂ -NH-C(O)-, -S-CH ₂ -CH(CH ₂ -OH)-NH-

S(O)-, -S-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O)-, -S-CH ₂ -CH(CH ₃ )-NH-S(O)-, -S-CH(CH ₃ )-CH ₂ -NH-S(O)-, -S-CH ₂ -

CH(CH ₂ -OH)-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -S-CH(CH ₃ )-CH ₂ -

NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -NH-CH ₂ -CH(CH ₃ )-NH-

C(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O)-, -

NH-CH ₂ -CH(CH ₃ )-NH-S(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-S(O)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-S(O ₂ )-, -NH-CH ₂ -

CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -NH-CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -O-(CH ₂ ) ₂ -NH-, -S-

(CH ₂ ) ₂ -NH-, -NH-(CH ₂ ) ₂ -NH-, -O-cyclohexyl-NH-C(O)-, -O-cyclohexyl-NH-S(O)-, -O-cyclohexyl-NH-S(O ₂ )-

, -O-cyclopentyl-NH-C(O)-, -O-cyclopentyl-NH-S(O)-, -O-cyclopentyl-NH-S(O ₂ )-, -S-cyclohexyl-NH-C(O)-

, -S-cyclohexyl-NH-S(O)-, -S-cyclohexyl-NH-S(O ₂ )-, -S-cyclopentyl-NH-C(O)-, -S-cyclopentyl-NH-S(O)-, -

S-cyclopentyl-NH-S(O ₂ )-, -NH-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-S(O)-, -NH-cyclohexyl-NH-

S(O ₂ )-, -NH-cyclopentyl-NH-C(O)-, -NH-cyclopentyl-NH-S(O)-, -NH-cyclopentyl-NH-S(O ₂ )-, -O- piperidinyl-C(O)-, -S-piperidinyl-C(O)-, -NH-piperidinyl-C(O)-, -O-piperidinyl-S(O)-, -S-piperidinyl-S(O)-,

-NH-piperidinyl-S(O)-, -O-piperidinyl-S(O ₂ )-, -S-piperidinyl-S(O ₂ )-, -NH-piperidinyl-S(O ₂ )-, -piperidinyl-

NH-C(O)-, -piperidinyl-NH-S(O)-, -piperidinyl-NH-S(O ₂ )-, -O-pyrrolidinyl-C(O)-NH-, -S-pyrrolidinyl-C(O)-

NH-, -NH-pyrrolidinyl-C(O)-NH-, -O-pyrrolidinyl-S(O)-NH-, -S-pyrrolidinyl-S(O)-NH-, -N H-pyrrolidinyl-

S(O)-NH-, -O-pyrrolidinyl-S(O ₂ )-NH-, -S-pyrrolidinyl-S(O ₂ )-NH-, -NH-pyrrolidinyl-S(O ₂ )-NH-, -o- pyrrolidinyl-CH ₂ -NH-C(O)-, -S-pyrrolidinyl-CH ₂ -NH-C(O)-, -NH-pyrrolidinyl-CH ₂ -NH-C(O)-, -o- pyrrolidinyl-CH ₂ -NH-S(O)-, -S-pyrrolidinyl-CH ₂ -NH-S(O)-, -NH-pyrrolidinyl-CH ₂ -NH-S(O)-, -o- pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -S-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -NH-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -o- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -s- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -o- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -S-tetrahydropyrimidyl- (e.g., -O-

1,4,5,6-Tetrahydropyrimidinyl-), -NH-tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -

O-CH2-; -S-CH2-; and -NH-CH2-.

More particularly, the compound of formula (B) has

Ri selected from the group consisting of a phenyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl , optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a C1-C3 alkyl optionally substituted by at least one halogen, by a C1-C3 alkyloxy optionally substituted by at least one halogen and/or by a halogen; a C3-C7 cycloalkyl, preferably a C ₅ -Cs cycloalkyl, more preferably a cyclohexyl, said cycloalkyl being optionally bridged and/or optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a C2-C6 alkyl optionally substituted by at least one halogen, and an ethynyl (-CECH),

XI, X2 and X3 selected in one of the following combinations: Xi, X2 and X3 are CH; Xi is CH and X2 and X3 are N; Xi is N and X2 and X3 are CH, and Xi and X2 are CH and X3 is N; preferably Xi is CH and X2 and X3 are N;

- -Y-L-B- selected in the group consisting of -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O ₂ )-NH-, -S-C(O)- NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O ₂ )-NH-, -S-CH ₂ -C(O)-NH-, -S-CH ₂ -S(O)-NH-, -S-CH2-S(O ₂ )- NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -S(O)-NH-, -0-CH2- S(O ₂ )-NH-, -NH-CH ₂ -C(O)-NH-, -NH-CH ₂ -S(O)-NH-, -NH-CH ₂ -S(O ₂ )-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O- (CH ₂ )2-N(CH ₃ )-C(O)-, -O-(CH ₂ )2-NH-S(O)-, -O-(CH ₂ )2-N(CH ₃ )-S(O)-, -O-(CH ₂ )2-NH-S(O ₂ )-, -O- (CH2)2-N(CH ₃ )-S(O ₂ )-, -S-(CH ₂ )2-NH-C(O)-, -S-(CH ₂ )2-N(CH ₃ )-C(O)-, -S-(CH ₂ )2-NH-S(O)-, -S-(CH ₂ ) ₂ - N(CH ₃ )-S(O)-, -S-(CH ₂ ) ₂ -NH-S(O ₂ )-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -NH-(CH ₂ ) ₂ -NH-C(O)-, -NH-(CH ₂ ) ₂ - N(CH ₃ )-C(O)-, -NH-(CH ₂ ) ₂ -NH-S(O)-, -NH-(CH ₂ )2-N(CH ₃ )-S(O)-, -NH-(CH ₂ ) ₂ -NH-S(O ₂ )-, -NH-(CH ₂ ) ₂ - N(CH ₃ )-S(O ₂ )-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH2-CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )- NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH- S(O)-, -O-CH ₂ -CH(CH ₃ )-NH-S(O)-, -O-CH(CH ₃ )-CH ₂ -NH-S(O)-, -O-CH ₂ -CH(CH2-OH)-NH-S(O ₂ )-, -O- CH ₂ -CH(CH2-OCH ₃ )-NH-S(O2)-, -O-CH2-CH(CH ₃ )-NH-S(O ₂ )-, -O-CH(CH ₃ )-CH2-NH-S(O ₂ )-, -S-CH2- CH(CH ₂ -OH)-NH-C(O)-, -S-CH2-CH(CH ₂ -OCH ₃ )-NH-C(O)-, -S-CH ₂ -CH(CH ₃ )-NH-C(O)-, -S-CH(CH ₃ )- CH ₂ -NH-C(O)-, -S-CH2-CH(CH ₂ -OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH ₃ )-NH-S(O)-, -S-CH ₂ -CH(CH ₃ )- NH-S(O)-, -S-CH(CH ₃ )-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O ₂ )-, -S-CH2-CH(CH ₂ -OCH ₃ )-NH- S(O ₂ )-, -S-CH2-CH(CH ₃ )-NH-S(O2)-, -S-CH(CH ₃ )-CH2-NH-S(O2)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, - NH-CH2-CH(CH ₂ -OCH ₃ )-NH-C(O)-, -NH-CH ₂ -CH(CH ₃ )-NH-C(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-C(O)-, - NH-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -NH-CH2-CH(CH ₂ -OCH ₃ )-NH-S(O)-, -NH-CH ₂ -CH(CH ₃ )-NH-S(O)-, - NH-CH(CH ₃ )-CH ₂ -NH-S(O)-, -NH-CH ₂ -CH(CH2-OH)-NH-S(O ₂ )-, -NH-CH ₂ -CH(CH2-OCH ₃ )-NH-S(O2)- , -NH-CH2-CH(CH ₃ )-NH-S(O ₂ )-, -NH-CH(CH ₃ )-CH2-NH-S(O ₂ )-, -O-(CH ₂ ) ₂ -NH-, -S-(CH ₂ ) ₂ -NH-, -NH- (CH ₂ ) ₂ -NH-, -O-cyclohexyl-NH-C(O)-, -O-cyclohexyl-NH-S(O)-, -O-cyclohexyl-NH-S(O ₂ )-, -O- cyclopentyl-NH-C(O)-, -O-cyclopentyl-NH-S(O)-, -O-cyclopentyl-NH-S(O ₂ )-, -S-cyclohexyl-NH- C(O)-, -S-cyclohexyl-NH-S(O)-, -S-cyclohexyl-NH-S(O ₂ )-, -S-cyclopentyl-NH-C(O)-, -S- cyclopentyl-NH-S(O)-, -S-cyclopentyl-NH-S(O ₂ )-, -NH-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH- S(O)-, -NH-cyclohexyl-NH-S(O2)-, -NH-cyclopentyl-NH-C(O)-, -NH-cyclopentyl-NH-S(O)-, -NH- cyclopentyl-NH-S(O2)-, -O-piperidinyl-C(O)-, -S-piperidinyl-C(O)-, -NH-piperidinyl-C(O)-, -O- piperidinyl-S(O)-, -S-piperidinyl-S(O)-, -NH-piperidinyl-S(O)-, -O-piperidinyl-S(O ₂ )-, -S- piperidinyl-S(O ₂ )-, -NH-piperidinyl-S(O ₂ )-, -piperidinyl-NH-C(O)-, -piperidinyl-NH-S(O)-, - piperidinyl-NH-S(O ₂ )-, -O-pyrrolidinyl-C(O)-NH-, -S-pyrrolidinyl-C(O)-NH-, -NH-pyrrolidinyl-

C(O)-NH-, -O-pyrrolidinyl-S(O)-NH-, -S-pyrrolidinyl-S(O)-NH-, -NH-pyrrolidinyl-S(O)-NH-, -O- pyrrolidinyl-S(O2)-NH-, -S-pyrrolidinyl-S(O2)-NH-, -NH-pyrrolidinyl-S(O2)-NH-, -O-pyrrolidinyl-

CH2-NH-C(O)-, -S-pyrrolidinyl-CH2-NH-C(O)-, -NH-pyrrolidinyl-CH2-NH-C(O)-, -O-pyrrolidinyl-

CH2-NH-S(O)-, -S-pyrrolidinyl-CH2-NH-S(O)-, -NH-pyrrolidinyl-CH2-NH-S(O)-, -O-pyrrolidinyl-

CH2-NH-S(O ₂ )-, -S-pyrrolidinyl-CH2-NH-S(O ₂ )-, -NH-pyrrolidinyl-CH2-NH-S(O ₂ )-, -O- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -S-tetrahydropyrimidyl- (e.g., - O-1,4,5,6-Tetrahydropyrimidinyl-), -NH-tetrahydropyrimidyl- (e.g., -0-1, 4,5,6-

Tetrahydropyrimidinyl-), -O-CH2-; -S-CH2-; and -NH-CH2-.; preferably selected from the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH2-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-CH ₂ - CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH2-CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )- CH ₂ -NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -O-CH2-CH2-NH-S(O ₂ )-, piperidinyl-NH-C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l, 4,5,6-

Tetrahydropyrimidinyl-NH-C(O)-), -O-tetrahydropyrimidyl- (e.g., -0-1, 4,5,6-

Tetrahydropyrimidinyl-), -O-CH2-CH2-NH-, -S-CH2-; more preferably selected from the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH2-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O- cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-; and

A being a ring selected from phenyl, pyridinyl, benzoxazolyl, benzothiazolyl, thiophenyl, thienopyridinyl, indolyl, isoindolinonyl, phthalimidyl and benzothiophenyl, said ring being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a pyrrolidonyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, said ring and Ci- Cg alkyl, preferably said Ci-Cg alkyl being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co-C ₃ alkyl-NH- C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, this substitution is not in a vicinal position of the ring with respect to the connecting bound of A to the rest of the compound.

In a more particular aspect, the compound of formula (B) has

Ri selected from the group consisting of a phenyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl , optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a Ci-C ₃ alkyl optionally substituted by at least one halogen, by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen and/or by a halogen; a C ₃ -C ₇ cycloalkyl, preferably a C ₅ -Cg cycloalkyl, more preferably a cyclohexyl, said cycloalkyl being optionally bridged and/or optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a C2-C6 alkyl optionally substituted by at least one halogen, and an ethynyl (-CECH),

XI being CH and X2 and X3 being N;

- -Y-L-B- selected in the group consisting of -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O ₂ )-NH-, -S-C(O)- NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O ₂ )-NH-, -S-CH ₂ -C(O)-NH-, -S-CH ₂ -S(O)-NH-, -S-CH2-S(O ₂ )- NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -S(O)-NH-, -0-CH2- S(O ₂ )-NH-, -NH-CH ₂ -C(O)-NH-, -NH-CH ₂ -S(O)-NH-, -NH-CH2-S(O ₂ )-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O- (CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -O-(CH ₂ ) ₂ -NH-S(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -O-(CH ₂ ) ₂ -NH-S(O ₂ )-, -O- (CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -S-(CH ₂ ) ₂ -NH-C(O)-, -S-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -S-(CH ₂ ) ₂ -NH-S(O)-, -S-(CH ₂ ) ₂ - N(CH ₃ )-S(O)-, -S-(CH ₂ ) ₂ -NH-S(O ₂ )-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -NH-(CH ₂ ) ₂ -NH-C(O)-, -NH-(CH ₂ ) ₂ - N(CH ₃ )-C(O)-, -NH-(CH ₂ ) ₂ -NH-S(O)-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -NH-(CH ₂ ) ₂ -NH-S(O ₂ )-, -NH-(CH ₂ ) ₂ - N(CH ₃ )-S(O ₂ )-, -O-CH2-CH(CH ₂ -OH)-NH-C(O)-, -O-CH2-CH(CH2-OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )- NH-C(O)-, -O-CH(CH ₃ )-CH2-NH-C(O)-, -O-CH2-CH(CH ₂ -OH)-NH-S(O)-, -O-CH2-CH(CH2-OCH ₃ )-NH- S(O)-, -O-CH2-CH(CH ₃ )-NH-S(O)-, -O-CH(CH ₃ )-CH2-NH-S(O)-, -O-CH2-CH(CH2-OH)-NH-S(O ₂ )-, -O- CH2-CH(CH2-OCH ₃ )-NH-S(O2)-, -O-CH2-CH(CH ₃ )-NH-S(O2)-, -O-CH(CH ₃ )-CH2-NH-S(O2)-, -S-CH2- CH(CH ₂ -OH)-NH-C(O)-, -S-CH2-CH(CH2-OCH ₃ )-NH-C(O)-, -S-CH2-CH(CH ₃ )-NH-C(O)-, -S-CH(CH ₃ )- CH ₂ -NH-C(O)-, -S-CH2-CH(CH ₂ -OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH ₃ )-NH-S(O)-, -S-CH ₂ -CH(CH ₃ )- NH-S(O)-, -S-CH(CH ₃ )-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O ₂ )-, -S-CH2-CH(CH2-OCH ₃ )-NH- S(O ₂ )-, -S-CH2-CH(CH ₃ )-NH-S(O2)-, -S-CH(CH ₃ )-CH2-NH-S(O2)-, -NH-CH2-CH(CH ₂ -OH)-NH-C(O)-, - NH-CH2-CH(CH2-OCH ₃ )-NH-C(O)-, -NH-CH2-CH(CH ₃ )-NH-C(O)-, -NH-CH(CH ₃ )-CH2-NH-C(O)-, - NH-CH2-CH(CH ₂ -OH)-NH-S(O)-, -NH-CH2-CH(CH2-OCH ₃ )-NH-S(O)-, -NH-CH2-CH(CH ₃ )-NH-S(O)-, - NH-CH(CH ₃ )-CH2-NH-S(O)-, -NH-CH2-CH(CH2-OH)-NH-S(O ₂ )-, -NH-CH2-CH(CH2-OCH ₃ )-NH-S(O2)- , -NH-CH2-CH(CH ₃ )-NH-S(O2)-, -NH-CH(CH ₃ )-CH2-NH-S(O2)-, -O-(CH ₂ ) ₂ -NH-, -S-(CH ₂ ) ₂ -NH-, -NH- (CH ₂ ) ₂ -NH-, -O-cyclohexyl-NH-C(O)-, -O-cyclohexyl-NH-S(O)-, -O-cyclohexyl-NH-S(O ₂ )-, -O- cyclopentyl-NH-C(O)-, -O-cyclopentyl-NH-S(O)-, -O-cyclopentyl-NH-S(O ₂ )-, -S-cyclohexyl-NH- C(O)-, -S-cyclohexyl-NH-S(O)-, -S-cyclohexyl-NH-S(O ₂ )-, -S-cyclopentyl-NH-C(O)-, -S- cyclopentyl-NH-S(O)-, -S-cyclopentyl-NH-S(O ₂ )-, -NH-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-

S(O)-, -NH-cyclohexyl-NH-S(O ₂ )-, -NH-cyclopentyl-NH-C(O)-, -NH-cyclopentyl-NH-S(O)-, -NH- cyclopentyl-NH-S(O ₂ )-, -O-piperidinyl-C(O)-, -S-piperidinyl-C(O)-, -NH-piperidinyl-C(O)-, -O- piperidinyl-S(O)-, -S-piperidinyl-S(O)-, -NH-piperidinyl-S(O)-, -O-piperidinyl-S(O ₂ )-, -S- piperidinyl-S(O ₂ )-, -NH-piperidinyl-S(O ₂ )-, -piperidinyl-NH-C(O)-, -piperidinyl-NH-S(O)-, - piperidinyl-NH-S(O ₂ )-, -O-pyrrolidinyl-C(O)-NH-, -S-pyrrolidinyl-C(O)-NH-, -NH-pyrrolidinyl-

C(O)-NH-, -O-pyrrolidinyl-S(O)-NH-, -S-pyrrolidinyl-S(O)-NH-, -NH-pyrrolidinyl-S(O)-NH-, -O- pyrrolidinyl-S(O ₂ )-NH-, -S-pyrrolidinyl-S(O ₂ )-NH-, -NH-pyrrolidinyl-S(O ₂ )-NH-, -O-pyrrolidinyl-

CH ₂ -NH-C(O)-, -S-pyrrolidinyl-CH ₂ -NH-C(O)-, -NH-pyrrolidinyl-CH ₂ -NH-C(O)-, -O-pyrrolidinyl-

CH ₂ -NH-S(O)-, -S-pyrrolidinyl-CH ₂ -NH-S(O)-, -NH-pyrrolidinyl-CH ₂ -NH-S(O)-, -O-pyrrolidinyl-

CH ₂ -NH-S(O ₂ )-, -S-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -NH-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -O- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -S-tetrahydropyrimidyl- (e.g., - O-1,4,5,6-Tetrahydropyrimidinyl-), -NH-tetrahydropyrimidyl- (e.g., -0-1, 4,5,6-

Tetrahydropyrimidinyl-), -O-CH ₂ -; -S-CH ₂ -; and -NH-CH ₂ -; preferably selected from the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-CH ₂ - CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )- CH ₂ -NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -O-CH ₂ -CH ₂ -NH-S(O ₂ )-, piperidinyl-NH-C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l, 4,5,6-

Tetrahydropyrimidinyl-NH-C(O)-), -O-tetrahydropyrimidyl- (e.g., -0-1, 4,5,6-

Tetrahydropyrimidinyl-), -O-CH ₂ -CH ₂ -NH-, -S-CH ₂ -; more preferably selected from the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O- cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-; and

A being a ring selected from phenyl, pyridinyl, benzoxazolyl, benzothiazolyl, thiophenyl, thienopyridinyl, indolyl, isoindolinonyl, phthalimidyl and benzothiophenyl, said ring being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a pyrrolidonyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, said ring and Ci- Cg alkyl, preferably said Ci-Cg alkyl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C ₃ alkyl-NH-C(0)-R, Co-C ₃ alkyl-NH- C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, this substitution is not in a vicinal position of the ring with respect to the connecting bound of A to the rest of the compound.

In a more particular aspect, the compound of formula (B) has

Ri being selected from the group consisting of a phenyl optionally substituted by at least one halogen, in ortho or para, preferably para, in particular at least one fluorine or chlorine, more preferably at least one fluorine; by a Ci-C ₃ alkyloxy, in, ortho, meta or para, preferably meta or ortho, optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl, in ortho or para, preferably ortho, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, in para optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a cyclohexyl, said cyclohexyl being optionally bridged and/or optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; preferably a bridged cyclohexyl; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; a C4-C6 alkyl optionally substituted by at least one halogen, preferably an isobutyl, an isopropyl or an isohexyl, and an ethynyl (-CECH),

XI being CH and X2 and X3 being N;

- Y-L-B- selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH- C(O)-, -NH-CH ₂ -CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ - OCH ₃ )-NH-C(O)-, - -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -O-cyclohexyl-NH- C(O)-, -O-cyclopentyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -O-CH ₂ -CH ₂ -NH-S(O ₂ )-, -O- piperidinyl-C(O)-, -piperidinyl-NH-C(O)-, -O-pyrrolidinyl-C(O)-NH-, -O-pyrrolidinyl-CH ₂ -NH- C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -O-CH ₂ -CH ₂ -NH-, and -S-CH ₂ -; and

A being a ring selected from the group consisting of phenyl, benzoxazolyl, 2-pyridinyl, 3- pyridinyl, isoindolinonyl, and thiophenyl, said ring being optionally substituted by a halogen, preferably a chlorine and/or a fluorine, by a hydroxy, by a nitro, by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably a methoxy, by a pyridinyl, preferably a 2- pyridinyl, by a morpholinyl, by a pyrrolidonyl, by a Co-C3alkyl-C(0)-OR, by a C1-C3 alkyl optionally substituted by at least one halogen, a guanidinyl, a Co-Csalkyl-NRR, a Co-Csalkyl-NH- C(O)-OR, a C ₀ -C ₃ alkyl-NH-C(O)-R, a C ₀ -C ₃ alkyl-NH-C(O)-NRR, with R being H or a C1-C4 alkyl optionally substituted by a group -NR'R' or OR', with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen, preferably Ci-C ₂ alkyl-NH ₂ , Ci-C ₂ alkyl-NH-C(O)- O-C1-C4 alkyl, Ci-C ₂ alkyl-NH-C(O)-Ci-C ₄ alkyl, Ci-C ₂ alkyl-NH-C(O)-NH ₂ , Ci-C ₂ alkyl-NH-C(O)-Ci- C ₄ alkyl-NH ₂ , and Ci-C ₂ alky l-NH-C(O)-Ci-C ₂ alkyl- N(CH ₃ ) ₂ .

In particular, the compound of formula (B) may have one of the following formulae:

with Ri, Y and A as defined above, Z being O, N or S, and n being an integer from 0 to 4, preferably being 1.

In a very specific aspect, the compound is selected in any of the Tables 1, 2 and 3.

In another a particular embodiment, the present invention relates to a compound for use as mentioned above, wherein the compound has a formula (C) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof

Cy-Y-L-B-A (C)

Wherein

- Cy is a ring selected from the group consisting of with X4, X ₅ and Xg being independently N or CH; R2 being a Ci-Cg alkyl, linear, branched or cyclic, optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; R3 being H or a C1-C3 alkyl optionally substituted by at least one halogen; and R4 being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; with X ₇ , Xg, and Xg being independently N or CR and at least one of X ₇ , Xg, and Xg is N, and X10 being CR, with R being H or a C1-C3 alkyl optionally substituted by a halogen, a hydroxy, a C1-C3 alkyloxy, or a NR'R' with R' being H or a C1-C3 alkyl; R ₇ being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; with Xu being a heteroatom, preferably S, O or NH, more preferably S, and X12 being N or CH and X13 being CH or N; Rs being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen;

- Y-L-B- is absent or selected from the group consisting of -S-CH2-C(O)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)- CH ₂ -, C(O)-NH-, -S-(CH ₂ ) ₃ - C(O)-NH-, -S-(CH ₂ )4-C(O)-NH-, -S-(CH ₂ ) ₂ -NH- C(O)-, -C(O)-piperazinyl-, - pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -S-CH2-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-CO-, -NH- CH ₂ -C(O)-NH-, -O-CH2-, -O-(CH ₂ ) ₂ -, -S-(CH ₂ ) ₃ -, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ )-C(O)-, - piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, -S-cyclohexyl-C(O)-NH-, -N(CH3)-CH2-C(O)-NH-, -C(O)-NH-, - CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₂ -C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, and - O-(CH ₂ )-C(O)-N(CH ₃ )-;

- A is a ring selected from the group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, a 5-10- membered heteroaryl, preferably a 9-membered heteroaryl, said ring being optionally substituted by substitution(s) selected from the group consisting of halogen, a cyano, hydroxy, an ethynyl (-CECH), nitro, amino, amido, a Ci-Cg alkyl optionally substituted by at least one halogen, an amino group, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C ₃ alkyl-NH-C(0)-R, Co-C ₃ alkyl-NH- C(O)-OR, Co-C ₃ alkyl-NH-C(0)- NRR, Co-C ₃ alkyl-C(0)-R, Co-C ₃ alkyl-C(0)-OR, or Co-C ₃ alkyl-NRR, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In a particular aspect, the compound of formula (C) for use as mentioned above may have a formula (C-l) with X4, X ₅ and Xg being N or CH; R ₂ being selected from the group consisting of a methyl, an ethyl, a n- propyl, an isopropyl, a n-butyl, an isobutyl, a tertbutyl, optionally substituted by at least one halogen, preferably a fluorine, or a methoxy; R ₃ being H or a methyl optionally substituted by a halogen, preferably a fluorine; R4 being H or a fluorine, R ₅ and Rg being H; and with -Y-L-B- being absent or selected from the group consisting of selected from the group consisting of -S-CH ₂ -C(O)-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -, C(O)-NH-, -S-(CH ₂ ) ₃ - C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH- , -S-(CH ₂ ) ₂ -NH- C(O)-, -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -S-CH ₂ -, -O-(CH ₂ ) ₂ - NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-CO-, -NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ )- C(O)-, - piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, -S-cyclohexyl-C(O)-NH-, -N(CH ₃ )-CH ₂ -C(O)-NH-, -C(O)- NH-, -CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₂ -C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, and -O-(CH2)-C(O)-N(CH3)-; preferably selected from the group consisting of -S-CH2-C(O)-NH-, -S(O)- CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH-, -S-(CH ₂ ) ₂ -NH-C(O)-, -C(O)- piperazinyl-, -pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, - NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ )-C(O)-, -piperazinyl-C(O)-, -O-2-oxo- pyrrolidinyl-, -S-cyclohexyl-C(O)-NH-, -NMe-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)- and -O- piperidinyl-C(O)-; more preferably selected from the group consisting of -S-CH2-C(O)-NH-, -S(O)-CH ₂ - C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH-, -S-(CH ₂ ) ₂ -NH-CO-, -C(O)- piperazinyl-, -pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -O-(CH2)2-NH-C(O)-, -O-(CH2)2-N(CH3)-C(O)-, - NH-CH2-C(O)-NH-, and -O-piperidinyl-C(O)- , and

A being a ring selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para, a phenyl substituted in para by a Co- C3alkyl-NH-C(O)-R, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, a morpholinyl, a piperazinyl or a piperidinyl optionally substituted by a methyl, and a cyclohexyl; or with -Y-L-B- being absent or selected from the group consisting of -O-CH2-, -S-CH2-, and -S-(CH2)3- and A being benzoxazolyl, benzothiazolyl, thienopyridinyl, benzothiophenyl, or indolyl, preferably benzoxazolyl or benzothiazolyl, preferably substituted by a halogen, in particular a chlorine, preferably in position 6.

The present application also relates to a new compound having the formula (C-l) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof with X ₄ , X ₅ and Xg being N or CH; R2 being selected from the group consisting of a methyl, an ethyl, a n- propyl, an isopropyl, a n-butyl, an isobutyl, a tertbutyl, optionally substituted by at least one halogen, preferably a fluorine, or a methoxy; R3 being H or a methyl optionally substituted by a halogen, preferably a fluorine; R ₄ being H or a fluorine, R ₅ and Rg being H; and with -Y-L-B- being absent or selected from the group consisting of selected from the group consisting of - C(O)-NH-, -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-CO-, - NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, - piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, - N(CH ₃ )-CH2-C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH-CH ₂ -C(O)-NH-, -O-(CH ₂ ) ₃ - C(O)-NH-, and -O-(CH2)-C(O)-N(CH3)-; preferably selected from the group consisting of -C(O)- piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)-NH-, -O- (CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, -NMe-CH ₂ -C(O)-NH-, - C(O)-NH-, -CH ₂ -NH-C(O)- and -O-piperidinyl-C(O)-; more preferably selected from the group consisting of -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ - C(O)-NH-, and -O-piperidinyl-C(O)- , and

A being a ring selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para, a phenyl substituted in para by a Co- C ₃ alkyl-NH-C(O)-R, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, a morpholinyl, a piperazinyl or a piperidinyl optionally substituted by a methyl, and a cyclohexyl; or with -Y-L-B- being absent or selected from the group consisting of -O-CH ₂ -, -S-CH ₂ -, and -S-(CH ₂ ) ₃ - and A being a benzoxazolyl or a benzothiazolyl substituted by a chlorine, preferably in position 6.

In another particular aspect, the compound of formula (C) for use as mentioned above may have a formula (C-2) with one of X ₇ and X ₈ being N and the other is CH, , Xg being CH or N and X10 being CRb, with Rb being H or a Ci-C ₃ alkyl optionally substituted by a halogen, a hydroxy, a Ci-C ₃ alkyloxy, or a NR'R' with R' being independently H or a Ci-C ₃ alkyl; R ₇ being H; with -Y-L-B- being selected from the group consisting of -O-CH ₂ -, -O-(CH ₂ ) ₂ -NH-C(O)-, -S-(CH ₂ ) ₂ -NH-CO- , -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -O-CH ₂ -C(O)-NH-, and -S-CH ₂ -C(O)-NH-, preferably selected from the group consisting of -O-CH ₂ -, -O-(CH ₂ ) ₂ -NH-C(O)-, and -S-(CH ₂ ) ₂ -NH-C(O)-; and with A being a ring selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (- CECH), and a cyano, a phenyl substituted by an aminomethyl in para which is optionally substituted by an a C ₂ -C ₃ acyl, a morpholinyl, a piperazinyl or a piperidinyl optionally substituted by a methyl, a cyclohexyl and a benzoxazolyl or a benzothiazolyl substituted by a chlorine, preferably in position 6, preferably selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para optionally substituted by an a C ₂ -C ₃ acyl.

In another particular aspect, the compound of formula (C) for use as mentioned above may have a formula (C-3) with Xu being S, O or NH, X12 and X13 being N or CH; Rs being H, a phenyl or a pyridinyl, in particular a 2-pyridinyl; with -Y-L-B- being absent or selected from the group consisting of -C(O)-NH-, and -CH2-NH-C(O)-; and with A being selected in the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para which is optionally substituted by an a C2-C3 acyl, and a benzoxazolyl substituted by a chlorine, preferably in position 6.

In another particular aspect, the compound of formula (C) for use as mentioned above is selected in any of the Tables 4, 5 and 6.

The present invention further relates to a new compound selected in Table 7, 8 or 9.

Finally, the present invention relates to a pharmaceutical composition comprising a new compound according to the present invention and to a new compound according to the present invention for use as a medicament.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds capable of reducing food intake and their uses as appetite suppressant, in particular for the treatment of a disease, disorder or condition selected from the group consisting of metabolic syndrome including obesity, diabetes, hypertension, NASH, dyslipidemia, eating disorders including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome and MOMO syndrome, cardiovascular diseases, and medication-induced weight gain. In addition, the present invention relates to new compounds, a pharmaceutical or veterinary composition comprising a new compound according to the disclosure and their uses as a drug.

Definitions

According to the present invention, the terms below have the following meanings:

The terms mentioned herein with prefixes such as for example Ci-Cg, can also be used with lower numbers of carbon atoms such as C1-C2. If, for example, the term Ci-Cg is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C4 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 4 carbon atoms, especially 1, 2, 3 or 4 carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms. C0-C3 means that the corresponding hydrocarbon chain may comprise from 0 to 3 carbon atoms, especially 0, 1, 2 or 3 carbon atoms. In particular, when in the context of Co, the hydrocarbon chain is absent.

The term "alkyl" refers to a saturated, linear or branched aliphatic group. The term "(Ci-Cg)alkyl" more specifically means methyl, ethyl, propyl, isopropyl, butyl, pentyl, or hexyl. The term "(Ci-C4)alkyl" more specifically means methyl, ethyl, propyl, or isopropyl. The term "(Ci-Csjalkyl" more specifically means methyl, ethyl or propyl. In a particular aspect, the "alkyl" is a methyl. By "Me", it refers to a methyl. The term "alkoxy" or "alkyloxy" corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond. (Ci-Cg)alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, pentyloxy, or hexyloxy. (Ci-C4)alkoxy includes methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy. (Ci-Csjalkoxy includes methoxy, ethoxy, propyloxy or isopropyloxy. In a particular aspect, the "alkoxy" or "alkyloxy" is a methoxy.

The term "cycloalkyl" corresponds to a saturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 20 atoms of carbons. It also includes fused, bridged, or spiro-connected cycloalkyl groups. The term "cycloalkyl" includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl. The term "spirocycloalkyl" includes for instance a spirocyclopentyl. In a particular aspect, the term "cycloalkyl" corresponds to a saturated monocycloalkyl group comprising between 3 and 7 atoms of carbons. In a particular aspect, the cycloalkyl group is cyclohexyl. The term "heterocycloalkyl" corresponds to a saturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen, oxygen, or sulphur atom, preferably at least one nitrogen atom or oxygen atom. It also includes fused, bridged, or spiro- connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, imidazolinyl, phthalimidyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidonyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydroisoquinoline, methyl-tetrahydroisoquinoline, isoindolinonyl, tetrahydrofuranyl, and tetrahydrothiophenyl. In a particular aspect, the heterocycloalkyl group is for instance azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or pyrrolidonyl. In another particular aspect, the heterocycloalkyl group is morpholinyl.

The term "aryl" corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term "aryl" includes phenyl, naphthyl, or anthracenyl. In a particular aspect, the aryl is a phenyl.

The term "heteroaryl" as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 5 and 14 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom. As used herein, the term "heteroaryl" further includes the "fused arylheteroaryl", "fused arylheterocycloalkyl" and "fused heteroarylcycloalkyl". The terms "fused arylheteroaryl" may for instance include non-exhaustively quinolinyl, indole, or benzoxazole. The terms "fused arylheterocycloalkyl" and "fused heteroarylcycloalkyl" correspond to a bicyclic group in which an aryl as above defined or a heteroaryl is respectively bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons. In other terms, the aryl or the heteroaryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly-cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienopyridinyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, p- carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotriazolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzothiazolyl, benzothiphenyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydropyridyl, pyrimidinyl, s- triazinyl, oxazolyl, or thiofuranyl. In a particular aspect, the heteroaryl is for instance pyridinyl, pyrimidyl, 1,2,4-triazinyl or benzoxazolyl. In a particular aspect, the heteroaryl is for instance tetrazolyl or 1,2,3-trizolyl. In a particular aspect, the heteroaryl is for instance thiophenyl.

The term "fused" when applied to the description of two rings corresponds to a bicyclic group in which the first ring is respectively bounded to the second ring by at least two carbons.

The term "halogen" corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, a chlorine or an iodine.

The expression "substituted by at least" or "substituted by" means that the group is substituted by one or several substituents of the list. For instance, the expression "a (Ci-Cg)alkyl substituted by at least one halogen" or "a (Ci-Cg)alkyl substituted by a halogen" may include a fluoromethyl (-CH2F), a difluoromethyl (-CHF2), or a trifluoromethyl (-CF3).

By "-CO-" or "-C(O)-", it refers to an oxo group. By "-SO-" or "-S(O)-", it refers to a sulfinyl group. By "- SO2-" or "-S(O ₂ )-", it refers to a sulfonyl group.

The expression "optionally substituted" means that the group is not substituted or substituted by one or several substituents of the list.

The "stereoisomers" are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, Cis-trans and E-Z isomers, conformers, and anomers. In a preferred embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers.

The "tautomers" are isomeric compounds that differ only in the position of the protons and the electrons.

The "pharmaceutically salts" include inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like. Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. In a preferred embodiment, the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate. The "pharmaceutically salts" also include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt. Representative examples of suitable salts with an organic base includes for instance a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. In a preferred embodiment, the salt is selected from the group consisting of sodium and potassium salt.

As used herein, the terms "treatment", "treat" or "treating" refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease. In certain aspects, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other aspects, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease.

As used herein, the terms "subject", "individual" or "patient" are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult and child. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.

The terms "quantity," "amount," and "dose" are used interchangeably herein and may refer to an absolute quantification of a molecule.

As used herein, the terms "active principle", "active ingredient" and "active pharmaceutical ingredient" are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect. As used herein, the term "therapeutic effect" refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder. As used herein, the term "effective amount" refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the disease, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor. In particular, an amount is effective, for example, when its administration results in one or more of weight loss, management of weight, suppression of appetite for food, control of food intake, loss of body fat, prevention or modulation of hypoglycaemia, prevention or modulation of hyperglycaemia, promotion of insulin synthesis, or reduction in food intake.

As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.

In a particular aspect of the present disclosure, the compound has the formula (A)

Cy-Y-L-B-A (A) and any pharmaceutical salt, stereoisomer, tautomer or solvate thereof wherein

Cy is a ring selected from the group consisting of with

- Ri is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a cyano, a hydroxy, an ethynyl (- CECH), an amino, and/or a halogen;

- Xi, X2 and X3 are independently N or CRa with Ra being independently selected from the group consisting of H, a C1-C3 alkyl optionally substituted by at least one halogen, and a halogen; b) with X4, X ₅ and Xg being independently N or CH; R2 being a Ci-Cg alkyl, linear, branched or cyclic, optionally substituted by a halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; R3, R4, Rs and Rg being independently selected from the group consisting of H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, and a C1-C3 alkoxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy; c) with X ₇ , Xg, and Xg being independently N or CRb and at least one of X ₇ , Xg, and Xg is N, and X10 being

CRb, with Rb being H or a C1-C3 alkyl optionally substituted by a halogen, a hydroxy, a C1-C3 alkyloxy, or a NR'R' with R' being H or a C1-C3 alkyl; R ₇ being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen or a C1-C3 alkyloxy; with Xu being a heteroatom, preferably S, O or NRc with Rc being H or a Ci-Cg alkyl optionally substituted by at least one halogen, more preferably S, X12 being N or CH and X13 being CH or N; Rg being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen or a C1-C3 alkyloxy;

- Y is present or absent and is selected from the group consisting of -S-, -NRd-, -O-, sulfinyl, sulfonyl, -

C(O)-NRd-, and -C(0)-, with Rd being H or C1-C3 alkyl optionally substituted by at least one halogen; - L is present or absent and is selected from the group consisting of a linear C1-C4 alkylenyl, optionally comprising a double or triple bound, and optionally substituted by a C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl, a heterocycloalkyl, an aryl and a heteroaryl, in particular a 5- or 6-membered cycloalkyl or heterocycloalkyl, especially a 5- or 6-membered heterocycloalkyl,

- B is present or absent and is selected from the group consisting of -NR _e -, -C(O)-NR _e -, -NR _e -C(O)-, - C(O)-, sulfinyl, sulfonyl, S(O)-NR _e -, -S(O2)-NR _e -, -NR _e -S(O)- and -NRe-SfCh)-, with R _e being H or a C1-C3 alkyl optionally substituted by at least one halogen,

- A is a ring selected from the group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and a 5-10- membered heteroaryl, said ring being optionally substituted by substitution(s) selected from the group consisting of a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, said ring, Ci- Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In a particular aspect of the present disclosure, the compound has the formula (B) and any pharmaceutical salt, stereoisomer, tautomer or solvate thereof wherein

- Ri is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a cyano, a hydroxy, an ethynyl (- CECH), an amino, and/or a halogen; - Xi, X2 and X3 are independently N or CRa with Ra being independently selected from the group consisting of H, a C1-C3 alkyl optionally substituted by at least one halogen, and a halogen;

- Y is present or absent and is selected from the group consisting of -S-, -NRd-, -O-, sulfinyl, sulfonyl, - C(O)-NRd-, and -C(O)-, with Rd being H or C1-C3 alkyl optionally substituted by at least one halogen;

- L is present or absent and is selected from the group consisting of a linear C1-C4 alkylenyl, optionally comprising a double or triple bound, and optionally substituted by a C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl, a heterocycloalkyl, an aryl and a heteroaryl, in particular a 5- or 6-membered cycloalkyl or heterocycloalkyl, especially a 5- or 6-membered heterocycloalkyl,

- B is present or absent and is selected from the group consisting of -NRe-, -C(O)-NRe-, -NRe-C(O)-, - C(O)-, sulfinyl, sulfonyl, S(O)-NRe-, -S(C>2)-NRe-, -NRe-S(O)- and -NRe-S(O2)-, with Re being H or a C1-C3 alkyl optionally substituted by at least one halogen,

- A is a ring selected from the group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and a 5-10- membered heteroaryl, said ring being optionally substituted by substitution(s) selected from the group consisting of a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, said ring, Ci- Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In a more particular aspect, the compound has a formula (B) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and

- Y is present or absent and is selected from the group consisting of S, -NH-, -O-, sulfinyl, and sulfonyl,

- L is present or absent and is selected from the group consisting of a linear C1-C2 alkylenyl, optionally comprising a double or triple bound, and optionally substituted by a C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl and a heterocycloalkyl, preferably a 5- or 6-membered cycloalkyl or heterocycloalkyl, - B is present or absent and is selected from the group consisting of -NR _e -, -NR _e -C(O)-, -C(O)-, -S(O)-, - S(O ₂ )-, -C(O)-NR _e -, -S(O)-NR _e -, -S(O ₂ )-NR _e -, -NR _e -S(O)-and -NR _e -S(O ₂ )-, with R _e being H or a C1-C3 alkyl optionally substituted by at least one halogen, and

- A is a ring selected from the group consisting of a phenyl, a 5-10-membered heteroaryl and a 5-10- membered heterocycloalkyl, said ring being optionally substituted by the substitution(s) being selected from the group consisting of halogen, cyano, hydroxy, ethynyl (-CECH), amino group, nitro, amido (- C(O)-NH ₂ ), guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, C ₀ -C ₃ alkyl-NH-C(O)-R, C ₀ -C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl- C(O)-OR, or Co-C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In a more particular aspect, the compound has a formula (B) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and

- Ri is selected from the group consisting of aryl, 6-10-membered heteroaryl, cycloalkyl, heterocycloalkyl, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a Ci-C ₃ alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a Ci-C ₃ alkyloxy, a cyano, a hydroxy, an ethynyl (-CECH), an amino, and/or a halogen.

In another more particular aspect, the compound has a formula (B) or a pharmaceutically acceptable salt, stereoisomer, tautomer or solvate thereof and

- Ri is selected from the group consisting of aryl, 6-10-membered heteroaryl, cycloalkyl, heterocycloalkyl, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a Ci-C ₃ alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a Ci-C ₃ alkyloxy, a cyano, a hydroxy, an ethynyl (-CECH), an amino, and/or a halogen;

- Y is present or absent and is selected from the group consisting of S, -NH-, -O-, sulfinyl, and sulfonyl,

- L is present or absent and is selected from the group consisting of a linear Ci-C ₂ alkylenyl, optionally comprising a double or triple bound, and optionally substituted by a Ci-C ₃ alkyl, the Ci-C ₃ alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl and a heterocycloalkyl, preferably a 5- or 6-membered cycloalkyl or heterocycloalkyl,

- B is present or absent and is selected from the group consisting of -NR _e -, -NR _e -C(O)-, -C(O)-, -S(O)-, - S(O ₂ )-, -C(O)-NR _e -, -S(O)-NR _e -, -S(O ₂ )-NR _e -, -NR _e -S(O)-and -NR _e -S(O ₂ )-, with R _e being H or a C1-C3 alkyl optionally substituted by at least one halogen, and

- A is a ring selected from the group consisting of a phenyl, a 5-10-membered heteroaryl and a 5-10- membered heterocycloalkyl, said ring being optionally substituted by the substitution(s) being selected from the group consisting of halogen, cyano, hydroxy, ethynyl (-CECH), amino group, nitro, amido, guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci- Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

YLB

In a particular aspect of the compounds of formula (B), -Y-L-B- is selected in the group consisting of - NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O ₂ )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)-NH-, -O-S(O ₂ )-NH-, -S- CH ₂ -C(O)-NH-, -S-CH ₂ -S(O)-NH-, -S-CH ₂ -S(O ₂ )-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -O-CH ₂ - C(O)-NH-, -O-CH ₂ -S(O)-NH-, -O-CH ₂ -S(O ₂ )-NH-, -NH-CH ₂ -C(O)-NH-, -NH-CH ₂ -S(O)-NH-, -NH-CH ₂ -S(O ₂ )- NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -O-(CH ₂ ) ₂ -NH-S(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -O-(CH ₂ ) ₂ - NH-S(O ₂ )-, -O-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -S-(CH ₂ ) ₂ -NH-C(O)-, -S-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -S-(CH ₂ ) ₂ -NH-S(O)-, -S- (CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -S-(CH ₂ ) ₂ -NH-S(O ₂ )-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -NH-(CH ₂ ) ₂ -NH-C(O)-, -NH-(CH ₂ ) ₂ - N(CH ₃ )-C(O)-, -NH-(CH ₂ ) ₂ -NH-S(O)-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -NH-(CH ₂ ) ₂ -NH-S(O ₂ )-, -NH-(CH ₂ ) ₂ -N(CH ₃ )- S(O ₂ )-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O- CH(CH ₃ )-CH ₂ -NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O)-, -O-CH ₂ -

CH(CH ₃ )-NH-S(O)-, -O-CH(CH ₃ )-CH ₂ -NH-S(O)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-S(O ₂ )-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )- NH-S(O ₂ )-, -O-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -O-CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -S-CH ₂ - CH(CH ₂ -OCH ₃ )-NH-C(O)-, -S-CH ₂ -CH(CH ₃ )-NH-C(O)-, -S-CH(CH ₃ )-CH ₂ -NH-C(O)-, -S-CH ₂ -CH(CH ₂ -OH)-NH- S(O)-, -S-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O)-, -S-CH ₂ -CH(CH ₃ )-NH-S(O)-, -S-CH(CH ₃ )-CH ₂ -NH-S(O)-, -S-CH ₂ -

CH(CH ₂ -OH)-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -S-CH(CH ₃ )-CH ₂ -

NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -NH-CH ₂ -CH(CH ₃ )-NH-

C(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O)-, -

NH-CH ₂ -CH(CH ₃ )-NH-S(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-S(O)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-S(O ₂ )-, -NH-CH ₂ -

CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -NH-CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -O-(CH ₂ ) ₂ -NH-, -S-

(CH ₂ ) ₂ -NH-, -NH-(CH ₂ ) ₂ -NH-, -O-cyclohexyl-NH-C(O)-, -O-cyclohexyl-NH-S(O)-, -O-cyclohexyl-NH-S(O ₂ )-

, -O-cyclopentyl-NH-C(O)-, -O-cyclopentyl-NH-S(O)-, -O-cyclopentyl-NH-S(O ₂ )-, -S-cyclohexyl-NH-C(O)-

, -S-cyclohexyl-NH-S(O)-, -S-cyclohexyl-NH-S(O ₂ )-, -S-cyclopentyl-NH-C(O)-, -S-cyclopentyl-NH-S(O)-, -

S-cyclopentyl-NH-S(O ₂ )-, -NH-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-S(O)-, -NH-cyclohexyl-NH-

S(O ₂ )-, -NH-cyclopentyl-NH-C(O)-, -NH-cyclopentyl-NH-S(O)-, -NH-cyclopentyl-NH-S(O ₂ )-, -O- piperidinyl-C(O)-, -S-piperidinyl-C(O)-, -NH-piperidinyl-C(O)-, -O-piperidinyl-S(O)-, -S-piperidinyl-S(O)-,

-NH-piperidinyl-S(O)-, -O-piperidinyl-S(O ₂ )-, -S-piperidinyl-S(O ₂ )-, -NH-piperidinyl-S(O ₂ )-, -piperidinyl-

NH-C(O)-, -piperidinyl-NH-S(O)-, -piperidinyl-NH-S(O ₂ )-, -O-pyrrolidinyl-C(O)-NH-, -S-pyrrolidinyl-C(O)-

NH-, -NH-pyrrolidinyl-C(O)-NH-, -O-pyrrolidinyl-S(O)-NH-, -S-pyrrolidinyl-S(O)-NH-, -N H-pyrrolidinyl-

S(O)-NH-, -O-pyrrolidinyl-S(O ₂ )-NH-, -S-pyrrolidinyl-S(O ₂ )-NH-, -NH-pyrrolidinyl-S(O ₂ )-NH-, -O- pyrrolidinyl-CH ₂ -NH-C(O)-, -S-pyrrolidinyl-CH ₂ -NH-C(O)-, -NH-pyrrolidinyl-CH ₂ -NH-C(O)-, -O- pyrrolidinyl-CH ₂ -NH-S(O)-, -S-pyrrolidinyl-CH ₂ -NH-S(O)-, -NH-pyrrolidinyl-CH ₂ -NH-S(O)-, -O- pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -S-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -NH-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -O- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -s- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -S-tetrahydropyrimidyl- (e.g., -O-

1,4,5,6-Tetrahydropyrimidinyl-), -NH-tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -

O-CH ₂ -; -S-CH ₂ -; and -NH-CH ₂ -.

In a more specific aspect of the compounds of formula (B), -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-CH ₂ -CH(CH ₂ -OH)-NH-

C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -O- cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -O-CH ₂ -CH ₂ -NH-S(O ₂ )-, piperidinyl-NH-C(O)-, -O- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -O-CH2-CH2-NH-, -S-CH2-.

In a very specific aspect of the compounds of formula (B), -Y-L-B- is selected from the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH2-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-, more preferably selected from the group consisting of -S-CH2-C(O)-NH-, -O- CH2-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-.

When -Y-L-B- includes a cyclohexyl, the two connecting bonds can be in positions 1 and 2, 1 and 3 or 1 and 4. When -Y-L-B- includes a cyclohexyl and the two connecting bonds are in positions 1 and 4, the two connecting bonds are in trans or cis configuration, preferably trans configuration. When -Y-L-B- includes a cyclohexyl and the two connecting bonds are in positions 1 and 2 or 1 and 3, the two connecting bonds are in trans configuration.

When -Y-L-B- includes a cyclopentyl, the two connecting bonds can be in positions 1 and 2 or 1 and 3, preferably 1 and 3. Preferably, the two connecting bonds are in trans configuration.

When -Y-L-B- includes a moiety -piperidinyl-C(O)-, -piperidinyl-C(O)- may have the following structure

When -Y-L-B- includes a moiety -piperidinyl-NH-, -piperidinyl-NH- has the following structure -Y-L-B- is -piperidinyl-NH-C(O)-, it may have the following structure

When -Y-L-B- includes a moiety -tetrahydropyrimidyl-, -tetrahydropyrimidyl- may have the following structure

For instance, when -Y-L-B- is -tetrahydropyrimidyl-C(O)-, it may have the following structure

When -Y-L-B- includes a moiety -pyrrolidinyl-C(O)-NH-, -pyrrolidinyl-C(O)-NH- has the following structure

When -Y-L-B- includes a moiety -pyrrolidinyl-CH ₂ -NH-, -pyrrolidinyl-CH ₂ -NH has the following structure

In a particular aspect, when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O ₂ )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, -O-S(O)- NH-, -O-S(O ₂ )-NH-, -S-CH ₂ -C(O)-NH-, -S-CH ₂ -S(O)-NH-, -S-CH ₂ -S(O ₂ )-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )- CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -S(O)-NH-, -O-CH ₂ -S(O ₂ )-NH-, -NH-CH ₂ -C(O)-NH-, -NH-CH ₂ -S(O)- NH-, -NH-CH ₂ -S(O ₂ )-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -O-(CH ₂ ) ₂ -NH-S(O)-, -O-(CH ₂ ) ₂ - N(CH ₃ )-S(O)-, -O-(CH ₂ ) ₂ -NH-S(O ₂ )-, -O-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -S-(CH ₂ ) ₂ -NH-C(O)-, -S-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -S-(CH ₂ ) ₂ -NH-S(O)-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -S-(CH ₂ ) ₂ -NH-S(O ₂ )-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -NH-(CH ₂ ) ₂ -NH- C(O)-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-(CH ₂ ) ₂ -NH-S(O)-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -NH-(CH ₂ ) ₂ -NH-S(O ₂ )-, - NH-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ - CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH- S(O)-, -O-CH ₂ -CH(CH ₃ )-NH-S(O)-, -O-CH(CH ₃ )-CH ₂ -NH-S(O)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-S(O ₂ )-, -O-CH ₂ - CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -O-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -O-CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ -OH)- NH-C(O)-, -S-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -S-CH ₂ -CH(CH ₃ )-NH-C(O)-, -S-CH(CH ₃ )-CH ₂ -NH-C(O)-, -S-CH ₂ - CH(CH ₂ -OH)-NH-S(O)-, -S-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O)-, -S-CH ₂ -CH(CH ₃ )-NH-S(O)-, -S-CH(CH ₃ )-CH ₂ -NH- S(O)-, -S-CH ₂ -CH(CH ₂ -OH)-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -S- CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -NH-CH ₂ - CH(CH ₃ )-NH-C(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -NH-CH ₂ -CH(CH ₂ - OCH ₃ )-NH-S(O)-, -NH-CH ₂ -CH(CH ₃ )-NH-S(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-S(O)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH- S(O ₂ )-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -NH-CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -O- (CH ₂ ) ₂ -NH-, -S-(CH ₂ ) ₂ -NH-, -NH-(CH ₂ ) ₂ -NH-, -O-cyclohexyl-NH-C(O)-, -O-cyclohexyl-NH-S(O)-, -O- cyclohexyl-NH-S(O ₂ )-, -O-cyclopentyl-NH-C(O)-, -O-cyclopentyl-NH-S(O)-, -O-cyclopentyl-NH-S(O ₂ )-, -S- cyclohexyl-NH-C(O)-, -S-cyclohexyl-NH-S(O)-, -S-cyclohexyl-NH-S(O ₂ )-, -S-cyclopentyl-NH-C(O)-, -S- cyclopentyl-NH-S(O)-, -S-cyclopentyl-NH-S(O ₂ )-, -NH-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-S(O)-, - NH-cyclohexyl-NH-S(O ₂ )-, -NH-cyclopentyl-NH-C(O)-, -NH-cyclopentyl-NH-S(O)-, -NH-cyclopentyl-NH- S(O ₂ )-, -O-piperidinyl-C(O)-, -S-piperidinyl-C(O)-, -NH-piperidinyl-C(O)-, -O-piperidinyl-S(O)-, -S- piperidinyl-S(O)-, -NH-piperidinyl-S(O)-, -O-piperidinyl-S(O ₂ )-, -S-piperidinyl-S(O ₂ )-, -NH-piperidinyl- S(O ₂ )-, -piperidinyl-NH-C(O)-, -piperidinyl-NH-S(O)-, -piperidinyl-NH-S(O ₂ )-, -O-pyrrolidinyl-C(O)-NH-, - S-pyrrolidinyl-C(O)-NH-, -NH-pyrrolidinyl-C(O)-NH-, -O-pyrrolidinyl-S(O)-NH-, -S-pyrrolidinyl-S(O)-NH-, -NH-pyrrolidinyl-S(O)-NH-, -O-pyrrolidinyl-S(O2)-NH-, -S-pyrrolidinyl-S(O2)-NH-, -NH-pyrrolidinyl-S(O2)-

NH-, -O-pyrrolidinyl-CH2-NH-C(O)-, -S-pyrrolidinyl-CH2-NH-C(O)-, -NH-pyrrolidinyl-CH2-NH-C(O)-, -O- pyrrolidinyl-CH2-NH-S(O)-, -S-pyrrolidinyl-CH2-NH-S(O)-, -NH-pyrrolidinyl-CH2-NH-S(O)-, -O- pyrrolidinyl-CH2-NH-S(O2)-, -S-pyrrolidinyl-CH2-NH-S(O2)-, -NH-pyrrolidinyl-CH2-NH-S(O2)-, -O- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH tetrahydropyrimidyl-NH-S(O2)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -S-tetrahydropyrimidyl- (e.g., -O-

1,4,5,6-Tetrahydropyrimidinyl-), and -NH-tetrahydropyrimidyl- (e.g., -0-1, 4,5,6-

Tetrahydropyrimidinyl-).

In another particular aspect, when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O- CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH2-CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )- CH ₂ -NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -O-CH2-CH ₂ -NH-S(O ₂ )-, piperidinyl- NH-C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), and -O-CH2-CH2-NH-.

In a more particular aspect, when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH2-CH2-NH-S(O ₂ )- , -O-CH2-CH2-NH-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )-NH- C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -NH-CH ₂ -CH ₂ -NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH- cyclohexyl-NH-C(O)-, -piperidinyl-NH-C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l, 4,5,6- Tetrahydropyrimidinyl-NH-C(O)-), and -O-tetrahydropyrimidyl- (e.g., -0-1, 4,5,6-

Tetrahydropyrimidinyl-).

In a very particular aspect, when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-.

In another particular aspect, when A is a 9-membered heteroaryl, -Y-L-B- is selected from the group consisting of -O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH2-CH2-NH-, -O-CH2- and -S-CH ₂ -, preferably is -O-CH2- or -S-

CH ₂ -. Ri definition

Ri can be selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a cyano, a hydroxy, an ethynyl (- CECH), an amino, and/or a halogen.

In a particular aspect, Ri is selected from the group consisting of aryl, 6-10-membered heteroaryl, cycloalkyl, heterocycloalkyl, and ethynyl (-CECH), said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl being optionally substituted by a Ci-Cg alkyl optionally substituted by at least one halogen or by a Ci- C3 alkyloxy, a Ci-Cg alkyloxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a cyano, a hydroxy, an ethynyl (-CECH), an amino, and/or a halogen.

In a more particular aspect, Ri is selected from the group consisting of a phenyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a C1-C3 alkyl optionally substituted by at least one halogen, by a C1-C3 alkyloxy optionally substituted by at least one halogen and/or by a halogen; a C3-C7 cycloalkyl, preferably a C ₅ -Cg cycloalkyl, more preferably a cyclohexyl, said cycloalkyl being optionally bridged and/or optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; and an ethynyl (-CECH).

In another particular aspect, Ri is selected from the group consisting of a phenyl optionally substituted by at least one halogen, in ortho or para, preferably para, in particular at least one fluorine or chlorine, more preferably at least one fluorine; by a C1-C3 alkyloxy, in, ortho, meta or para, preferably meta or ortho, optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl, in ortho or para, preferably ortho, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, in para optionally substituted by a halogen, in particular a fluorine, iodine or chorine, more preferably a fluorine; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a cyclohexyl, said cyclohexyl being optionally bridged and/or optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a Ci- C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; preferably a bridged cyclohexyl; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; and an ethynyl (-CECH). In a more specific aspect, Ri is selected from the group consisting of a 2-pyridinyl, optionally substituted in ortho or para by a halogen, in particular a fluorine; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a phenyl, optionally substituted, preferably in para or ortho, by one or two halogens, in particular a fluorine, or by an alkyloxy, preferably a methyloxy or an isopropyloxy, more preferably an isopropyloxy; a pyrimidyl, preferably a 2-pyrimidyl, a morpholinyl; and a cyclohexyl.

In a very specific aspect, Ri is selected from the group consisting of a 2-pyridinyl, optionally substituted in ortho or para by a halogen, in particular a fluorine; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a phenyl, optionally substituted in para by a halogen, in particular a fluorine, or by an alkyloxy, preferably a methyloxy or an isopropyloxy, more preferably an isopropyloxy; a pyrimidyl, preferably a 2-pyrimidyl, a morpholinyl; and a cyclohexyl.

Definition of Xi, X2 and X3

Xi, X2 and X3 are independently N or CRa with Ra being independently selected from the group consisting of H, a C1-C3 alkyl optionally substituted by at least one halogen, and a halogen.

In one aspect, Xi, X2 and X3 are N. In another aspect, Xi, X2 and X3 are CR _a and R _a is H. In another aspect, Xi and X2 are CR _a with Ra being H and X3 is N. In an addition aspect, Xi is CR _a with R _a being H and X2 and X3 are N. In another addition aspect, X2 is CR _a with R _a being H and Xi and X3 are N. In a further additional aspect, Xi is CR _a with R _a being a C1-C3 alkyl, especially a methyl, and X2 and X3 are N.

In a preferred aspect, Xi, X2 and X3 are as following:

Xi, X2 and X3 are CH; or

Xi is CH and X2 and X3 are N; or

Xi and X2 are CH and X3 is N.

In a preferred aspect, Xi, X2 and X3 are as following:

Xi, X2 and X3 are CH; or

Xi is CH and X2 and X3 are N.

In a very preferred aspect, Xi is CH and X2 and X3 are N.

Definition of A

A is a ring selected from the group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and a 5-10- membered heteroaryl, said ring being optionally substituted by substitution(s) selected from the group consisting of a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, said ring, Ci- Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C ₃ alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In a particular aspect, A is a ring selected from the group consisting of a phenyl, a 5-10-membered heteroaryl and a 5-10-membered heterocycloalkyl, said ring being optionally substituted by the substitution(s) being selected from the group consisting of halogen, cyano, hydroxy, ethynyl (-CECH), amino group, nitro, amido, guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, C ₀ -C ₃ alkyl-NH-C(O)-R, C ₀ -C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl- C(O)-OR, or Co-C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In one aspect, A is a ring selected from the group consisting of a phenyl, a 5-membered heteroaryl, a 6-membered heteroaryl, a 9-membered heteroaryl and a 10-membered heteroaryl, wherein the 5- membered heteroaryl can be preferably selected from the group consisting of thiophenyl, furanyl, and pyrrolyl; the 6-membered heteroaryl can be pyridinyl or pyrimidinyl, preferably pyridinyl; the 9- membered heteroaryl can be preferably selected from the group consisting of benzoxazolyl, benzimidazolyl, benzothiophenyl, indolyl, isoindolinonyl, and benzothiazolyl; and the 10-membered heteroaryl can be preferably selected from the group consisting of quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, and quinolinonyl, isoquinolinonyl, tetrahydroisoquinoline, and methyltetrahydroisoquinoline.

In a preferred aspect, A is substituted ring.

In a preferred aspect, A is a ring selected from optionally substituted a phenyl, a thiophenyl, a 2- pyridinyl, a 3-pyridinyl, a benzoxazolyl, a benzothiazolyl, a thiophenyl, a thienopyridinyl, an indolyl, an isoindolinonyl a phthalimidyl and a benzothiophenyl, preferably a substituted phenyl, pyridinyl, benzoxazolyl and thiophenyl.

In a very particular aspect, A is an optionally substituted phenyl, thiophenyl, an isoindolinonyl, 2- pyridinyl or 3- pyridinyl, preferably a substituted phenyl, thiophenyl, 2- pyridinyl or 3- pyridinyl.

The substitution of the ring A can be selected from a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, C ₀ -C ₃ alkyl-NH-C(O)-R, C ₀ -C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl- C(O)-OR, or Co-C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen.

Preferably, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, this substitution is not in a vicinal position of the ring with respect to the connecting bound of A to the rest of the compound. More preferably, this substitution is in para position of the ring with respect to the connecting bound of A to the rest of the compound.

More particularly, the substitution of the ring A can be selected from the group consisting of a halogen, optionally a chlorine, a iodine or a fluorine, preferably a fluorine or chlorine, more preferably a chlorine; a hydroxy, a cyano; a nitro; a Ci-Cg alkyl optionally substituted by at least one halogen; an amine; an amido; a nitro; a heterocycloalkyl such as morpholinyl; a guanidinyl; -NRR, -NH-C(O)-R, -NH-C(O)-Ci-C4alk-NR2, with R being independently H or a C1-C4 alkyl; a Ci-Cg alkyloxy optionally substituted by at least one halogen; and a heterocycloalkyl such as morpholinyl, or pyrrolidinyl, or pyrrolidonyl.

In a very specific embodiment, A is a phenyl, a 5-membered heteroaryl, a 6-membered heteroaryl, or a 9-membered heteroaryl substituted by a chlorine. For instance, A can be a phenyl, a thiophenyl, a 2- pyridinyl, a 3-pyridinyl, a benzoxazolyl, a benzothiazolyl, a thiophenyl, a thienopyridinyl, an indolyl, a phthalimidyl and a benzothiophenyl substituted by a chlorine, preferably in position para.

For instance, A could be a phenyl, optionally substituted by one or several substituents selected from the group consisting of a halogen, especially a chlorine, a fluorine or an iodine, preferably a chlorine, in particular in position para; optionally with an addition substitution by a halogen, preferably in meta, more preferably a fluorine in meta, or by a hydroxy, preferably in ortho; a Ci-Cg alkyl optionally substituted by at least one halogen; an amine; an amido; a nitro; a heterocycloalkyl such as morpholinyl or pyrrolidonyl,; a guanidinyl; -NRR, -NH-C(O)-R, -NH- C(O)-Ci-C4alk-NR2, with R being independently H or a C1-C4 alkyl; a Ci-Cg alkyloxy optionally substituted by a halogen, preferably a methoxy, a nitro, and a hydroxy, preferably in ortho.

A could also be a phenyl, optionally substituted by one or several substituents selected from the group consisting of Co-C3alkyl-C(0)-OR, Co-C3alkyl-C(0)-R, with R being independently H or a C1-C4 alkyl optionally substituted by NR'R' or OR' with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen.

Accordingly, A could be selected from the group consisting of a phenyl; a phenyl substituted in para by a chlorine, a fluorine, a methyl, a morpholinyl, -CH2-NH2, -(CH2)2-NH2, -CH2-N(CH3)2, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-guanidinyl, by -CH2-C(O)-NH2, -C(O)-NH2, a methoxy, -CH2-NH-C(O)-CH3, -CH2- NH-C(O)-CH2-NH ₂ , -CH2-NH-C(O)-CH(iPr)-NH2, -CH2-NH-C(O)-CH2-N(CH ₃ )2, nitro, -(CH ₂ )2-NH-C(O)-CH3; a phenyl substituted in para by a chlorine and in meta by a fluorine or a methoxy; a phenyl substituted in para by a chlorine and in ortho by a hydroxy, a cyano or a methyl; a phenyl substituted in meta by a chlorine; a 2-pyridinyl; a 2-pyridinyl substituted in para by a chlorine; a 3-pyridinyl; a 3-pyridinyl substituted in para by a chlorine; a 4-pyridinyl; a piperidinyl; a piperidinyl substituted by a methyl; a morpholinyl; a thiophenyl substituted by a halogen, preferably a chlorine; a thiophenyl substituted by a methyl; a benzoxazolyl substituted by a chlorine; a benzothiazolyl substituted by a chlorine; an indolyl substituted by a chlorine; a phthalimidyl and a thienopyridinyl.

In a more particular aspect, A could be selected from the group consisting of a phenyl, a phenyl substituted in para by a chlorine; a phenyl substituted in para by a chlorine and in meta by a fluorine, a methoxy, or a hydroxy; a phenyl substituted in para by a chlorine and in ortho by a hydroxy, a methoxy, a fluorine, or a methyl; a phenyl substituted in para by a fluorine, a methyl, a methoxy, -CH ₂ - NH-C(O)-CH ₃ , -CH ₂ -CH2-NH-C(O)-CH3,-CH2-NH ₂ , -CH ₂ -morpholinyl, -CH ₂ -guanidinyl, -C(O)-NH ₂ , -CH ₂ -NH- C(O)-CH(iPr)-NH ₂ , a morpholinyl, or a nitro; a phenyl substituted in meta by a chlorine; a 2-pyridinyl substituted in para by a chlorine; a 3-pyridinyl substituted in para by a chlorine; a benzoxazolyl substituted by a chlorine; thiophenyl substituted by a chlorine; a benzothiophenyl substituted by a halogen, preferably a chlorine, an indolyl substituted by a chlorine; a benzothiazolyl substituted by a chlorine; and a phthalim idyl.

In a very specific aspect, A could be selected from the group consisting of a phenyl substituted in para by a chlorine, a phenyl substituted in para by a chlorine and in meta by a fluorine, a phenyl substituted in para by a chlorine and by a hydroxy in ortho, a phenyl substituted in para by -CH ₂ -NH-C(O)-CH3, a phenyl substituted in para by a nitro, a 2- pyridinyl substituted in para by a chlorine, and a thiophenyl substituted by a halogen, preferably a chlorine.

In a particular aspect, the compound of formula (B) has

Ri is selected from the group consisting of a phenyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a C1-C3 alkyl optionally substituted by at least one halogen, by a C1-C3 alkyloxy optionally substituted by at least one halogen and/or by a halogen; a C3-C7 cycloalkyl, preferably a C ₅ -Cg cycloalkyl, more preferably a cyclohexyl, said cycloalkyl being optionally bridged and/or optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; and an ethynyl (-CECH);

XI, X2 and X3 are selected in one of the following combinations: Xi, X2 and X3 are N; Xi, X2 and X3 are CH; Xi and X2 are CH and X3 is N; Xi is CH and X2 and X3 are N; X2 is CH and Xi and X3 are N; and Xi is CR _a with R _a being a C1-C3 alkyl, especially a methyl, and X2 and X3 are N;

-Y-L-B- is such that when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -NH-C(O)-NH-, -NH-S(O)-NH-, -NH-S(O ₂ )-NH-, -S-C(O)-NH-, -O-C(O)-NH-, - O-S(O)-NH-, -O-S(O ₂ )-NH-, -S-CH ₂ -C(O)-NH-, -S-CH ₂ -S(O)-NH-, -S-CH ₂ -S(O ₂ )-NH-, -S(O)- CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -S(O)-NH-, -O-CH ₂ -S(O ₂ )- NH-, -NH-CH ₂ -C(O)-NH-, -NH-CH ₂ -S(O)-NH-, -NH-CH ₂ -S(O ₂ )-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, - O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -O-(CH ₂ ) ₂ -NH-S(O)-, -O-(CH ₂ )2-N(CH ₃ )-S(O)-, -O-(CH ₂ ) ₂ -NH-S(O ₂ )- , -O-(CH ₂ )2-N(CH ₃ )-S(O2)-, -S-(CH ₂ ) ₂ -NH-C(o)-, -S-(CH ₂ )2-N(CH ₃ )-C(O)-, -S-(CH ₂ ) ₂ -NH- S(O)-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, -S-(CH ₂ ) ₂ -NH-S(O ₂ )-, -S-(CH ₂ ) ₂ -N(CH ₃ )-S(O ₂ )-, -NH-(CH ₂ ) ₂ - NH-C(O)-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-(CH ₂ ) ₂ -NH-S(O)-, -NH-(CH ₂ ) ₂ -N(CH ₃ )-S(O)-, - NH-(CH ₂ )2-NH-S(O ₂ )-, -NH-(CH ₂ )2-N(CH ₃ )-S(O2)-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -0-CH2- CH(CH ₂ -OCH ₃ )-NH-C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -0-CH2- CH(CH ₂ -OH)-NH-S(O)-, -O-CH2-CH(CH ₂ -OCH ₃ )-NH-S(O)-, -O-CH ₂ -CH(CH ₃ )-NH-S(O)-, -O- CH(CH ₃ )-CH ₂ -NH-S(O)-, -O-CH ₂ -CH(CH2-OH)-NH-S(O ₂ )-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-

S(O ₂ )-, -O-CH2-CH(CH ₃ )-NH-S(O ₂ )-, -O-CH(CH ₃ )-CH2-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ -OH)-NH- C(O)-, -S-CH2-CH(CH ₂ -OCH ₃ )-NH-C(O)-, -S-CH ₂ -CH(CH ₃ )-NH-C(O)-, -S-CH(CH ₃ )-CH ₂ -NH- C(O)-, -S-CH2-CH(CH ₂ -OH)-NH-S(O)-, -S-CH2-CH(CH2-OCH ₃ )-NH-S(O)-, -S-CH ₂ -CH(CH ₃ )- NH-S(O)-, -S-CH(CH ₃ )-CH2-NH-S(O)-, -S-CH2-CH(CH2-OH)-NH-S(O ₂ )-, -S-CH ₂ -CH(CH ₂ - OCH ₃ )-NH-S(O ₂ )-, -S-CH2-CH(CH ₃ )-NH-S(O2)-, -S-CH(CH ₃ )-CH2-NH-S(O2)-, -NH-CH2- CH(CH ₂ -OH)-NH-C(O)-, -NH-CH2-CH(CH ₂ -OCH ₃ )-NH-C(O)-, -NH-CH ₂ -CH(CH ₃ )-NH-C(O)-, - NH-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-CH ₂ -CH(CH ₂ -OH)-NH-S(O)-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )- NH-S(O)-, -NH-CH ₂ -CH(CH ₃ )-NH-S(O)-, -NH-CH(CH ₃ )-CH ₂ -NH-S(O)-, -NH-CH ₂ -CH(CH ₂ - OH)-NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₂ -OCH ₃ )-NH-S(O ₂ )-, -NH-CH ₂ -CH(CH ₃ )-NH-S(O ₂ )-, -NH- CH(CH ₃ )-CH ₂ -NH-S(O ₂ )-, -O-(CH ₂ ) ₂ -NH-, -S-(CH ₂ ) ₂ -NH-, -NH-(CH ₂ ) ₂ -NH-, -O-cyclohexyl- NH-C(O)-, -O-cyclohexyl-NH-S(O)-, -O-cyclohexyl-NH-S(O ₂ )-, -O-cyclopentyl-NH-C(O)-, -O-cyclopentyl-NH-S(O)-, -O-cyclopentyl-NH-S(O ₂ )-, -S-cyclohexyl-NH-C(O)-, -S- cyclohexyl-NH-S(O)-, -S-cyclohexyl-NH-S(O ₂ )-, -S-cyclopentyl-NH-C(O)-, -S- cyclopentyl-NH-S(O)-, -S-cyclopentyl-NH-S(O ₂ )-, -NH-cyclohexyl-NH-C(O)-, -NH- cyclohexyl-NH-S(O)-, -NH-cyclohexyl-NH-S(O ₂ )-, -NH-cyclopentyl-NH-C(O)-, -NH- cyclopentyl-NH-S(O)-, -NH-cyclopentyl-NH-S(O ₂ )-, -O-piperidinyl-C(O)-, -S-piperidinyl- C(O)-, -NH-piperidinyl-C(O)-, -O-piperidinyl-S(O)-, -S-piperidinyl-S(O)-, -NH-piperidinyl- S(O)-, -O-piperidinyl-S(O ₂ )-, -S-piperidinyl-S(O ₂ )-, -NH-piperidinyl-S(O ₂ )-, -piperidinyl- NH-C(O)-, -piperidinyl-NH-S(O)-, -piperidinyl-NH-S(O ₂ )-, -O-pyrrolidinyl-C(O)-NH-, -S- pyrrolidinyl-C(O)-NH-, -NH-pyrrolidinyl-C(O)-NH-, -O-pyrrolidinyl-S(O)-NH-, -S- pyrrolidinyl-S(O)-NH-, -NH-pyrrolidinyl-S(O)-NH-, -O-pyrrolidinyl-S(O ₂ )-NH-, -S- pyrrolidinyl-S(O ₂ )-NH-, -NH-pyrrolidinyl-S(O ₂ )-NH-, -O-pyrrolidinyl-CH ₂ -NH-C(O)-, -S- pyrrolidinyl-CH ₂ -NH-C(O)-, -NH-pyrrolidinyl-CH ₂ -NH-C(O)-, -O-pyrrolidinyl-CH ₂ -NH- S(O)-, -S-pyrrolidinyl-CH ₂ -NH-S(O)-, -NH-pyrrolidinyl-CH ₂ -NH-S(O)-, -O-pyrrolidinyl- CH ₂ -NH-S(O ₂ )-, -S-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -NH-pyrrolidinyl-CH ₂ -NH-S(O ₂ )-, -O- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-C(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -NH- tetrahydropyrimidyl-NH-S(O)- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -S- tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), - NH-tetrahydropyrimidyl-NH-S(O ₂ )- (e.g., -O-l,4,5,6-Tetrahydropyrimidinyl-NH-C(O)-), -O-tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), -S- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-), and -NH- tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-); or when A is a 9-membered heteroaryl, -Y-L-B- is selected from the group consisting of - O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH ₂ -CH ₂ -NH-, -O-CH2- and -S-CH ₂ -, preferably is -O-CH2- or - S-CH ₂ -, and A is a ring selected from the group consisting of a phenyl, a 5-membered heteroaryl, a 6- membered heteroaryl and a 9-membered heteroaryl, wherein the 5-membered heteroaryl is selected from the group consisting of thiophenyl, furanyl, and pyrrolyl, preferably thiophenyl; the 6-membered heteroaryl is pyridinyl or pyrimidinyl, preferably pyridinyl; and the 9- membered heteroaryl is selected from the group consisting of benzoxazolyl, benzothiophenyl, indolyl, phthalimidyl and benzothiazolyl, preferably a substituted ring; the substitution being selected from the group consisting of a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C ₃ alkyl-NH-C(0)- R, C ₀ -C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C _o - C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen.

In another particular aspect, the compound of formula (B) has

Ri is selected from the group consisting of a phenyl optionally substituted by at least one halogen, in ortho or para, preferably para, in particular at least one fluorine or chlorine, more preferably at least one fluorine; by a Ci-C ₃ alkyloxy, in, ortho, meta or para, preferably meta or ortho, optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl, in ortho or para, preferably ortho, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, in para optionally substituted by a halogen, in particular a fluorine, iodine or chorine, more preferably a fluorine; by a Ci-C ₃ alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a cyclohexyl, said cyclohexyl being optionally bridged and/or optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; preferably a bridged cyclohexyl; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; and an ethynyl (-CECH);

XI, X2 and X3 are selected in one of the following combinations: Xi, X2 and X3 are CH; Xi and X2 are CH and X3 is N; Xi is CH and X2 and X3 are N; X2 is CH and Xi and X3 are N; and Xi is CR _a with R _a being a C1-C3 alkyl, especially a methyl, and X2 and X3 are N;

-Y-L-B- is such that when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH2-CH2- NH-S(O ₂ )-, -O-CH2-CH2-NH-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH2-CH(CH ₂ -OCH ₃ )-NH- C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -NH-CH2- CH2-NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -piperidinyl-NH- C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -0-1,4,5,6-Tetrahydropyrimidinyl-NH- C(O)-), and -O-tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-); or when A is a 9-membered heteroaryl, -Y-L-B- is selected from the group consisting of - O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH2-CH2-NH-, -O-CH2- and -S-CH ₂ -, preferably is -O-CH2- or - S-CH2-; and

A is a ring selected from the group consisting of a phenyl, a 5-membered heteroaryl, a 6- membered heteroaryl, and a 9-membered heteroaryl; the ring being substituted by one or several substitution(s) selected from the group consisting of halogen, cyano, hydroxy, ethynyl (-CECH), amino group, nitro, amido, guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said ring, Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C ₃ alkyl-NH-C(0)- R, C ₀ -C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C _o - C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen.

In another particular aspect, the compound of formula (B) has

Ri is selected from the group consisting of a 2-pyridinyl, optionally substituted in ortho or para by a halogen, in particular a fluorine; or a Ci-C ₃ alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a phenyl, optionally substituted, preferably in para or ortho, by one or two halogens, in particular a fluorine, or by an alkyloxy, preferably a methyloxy or an isopropyloxy, more preferably an isopropyloxy; a pyrimidyl, preferably a 2-pyrimidyl, a morpholinyl; and a cyclohexyl;

Xi, X2 and X ₃ are as following: Xi, X2 and X ₃ are CH; or Xi is CH and X2 and X ₃ are N; or Xi and X2 are CH and X ₃ is N; preferably Xi, X2 and X ₃ are CH; or Xi is CH and X2 and X ₃ are N; more preferably Xi is CH and X2 and X ₃ are N;

-Y-L-B- is such that when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH2-CH2- NH-S(O ₂ )-, -O-CH2-CH2-NH-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH- C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -NH-CH2- CH2-NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -piperidinyl-NH- C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -0-1,4,5,6-Tetrahydropyrimidinyl-NH- C(O)-), and -O-tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-); preferably selected in the group consisting of -S-CH2-C(O)-NH-, -O-CH2-CH2-NH-C(O)-, -NH-C(O)-NH-, -O-cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-; or when A is a 9-membered heteroaryl, -Y-L-B- is selected from the group consisting of - O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH ₂ -CH ₂ -NH-, -O-CH2- and -S-CH ₂ -, preferably is -O-CH2- or - S-CH ₂ -;

A is a ring selected from optionally substituted a phenyl, a thiophenyl, a 2-pyridinyl, a 3- pyridinyl, a benzoxazolyl, a benzothiazolyl, a thiophenyl, a thienopyridinyl, an indolyl, an isoindolinonyl, and a benzothiophenyl, preferably a substituted phenyl, pyridinyl, benzoxazolyl and thiophenyl; the ring being substituted by being substituted by one or several substitution(s) selected from the group consisting of halogen, cyano, hydroxy, ethynyl (-CECH), amino group, nitro, amido, guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said ring Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, preferably said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C ₃ alkyl-NH-C(0)- R, C ₀ -C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C _o - C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen.

In another particular aspect, the compound of formula (B) has

Ri is selected from the group consisting of a 2-pyridinyl, optionally substituted in ortho or para by a halogen, in particular a fluorine; or a Ci-C ₃ alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a phenyl, optionally substituted in para by a halogen, in particular a fluorine, or by an alkyloxy, preferably a methyloxy or an isopropyloxy, more preferably an isopropyloxy; a pyrimidyl, preferably a 2-pyrimidyl, a morpholinyl; and a cyclohexyl;

Xi, X ₂ and X ₃ are as following: Xi, X ₂ and X ₃ are CH; or Xi is CH and X ₂ and X ₃ are N; or Xi and X ₂ are CH and X ₃ is N; preferably Xi, X ₂ and X ₃ are CH; or Xi is CH and X ₂ and X ₃ are N; more preferably Xi is CH and X ₂ and X ₃ are N;

-Y-L-B- is such that when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH ₂ -CH ₂ - NH-S(O ₂ )-, -O-CH ₂ -CH ₂ -NH-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH ₂ -CH(CH ₂ -OCH ₃ )-NH- C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -NH-CH ₂ - CH ₂ -NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -piperidinyl-NH- C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -0-1,4,5,6-Tetrahydropyrimidinyl-NH- C(O)-), and -O-tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-); preferably selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -O-cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-; or when A is a 9-membered heteroaryl, -Y-L-B- is selected from the group consisting of - O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH ₂ -CH ₂ -NH-, -O-CH2- and -S-CH ₂ -, preferably is -O-CH2- or - S-CH ₂ -;

A is a ring selected from optionally substituted a phenyl, a thiophenyl, a 2-pyridinyl, a 3- pyridinyl, an isoindolinonyl, a benzoxazolyl, a benzothiazolyl, a thiophenyl, a thienopyridinyl, an indolyl, and a benzothiophenyl, preferably a substituted phenyl, pyridinyl, benzoxazolyl and thiophenyl; the ring being substituted by one or several substituents selected from the group consisting of a halogen, optionally a chlorine, an iodine or a fluorine, preferably a fluorine or chlorine, more preferably a chlorine; a hydroxy, a cyano; a nitro; a Ci-Cg alkyl optionally substituted by at least one halogen; an amine; an amido; a nitro; a heterocycloalkyl such as morpholinyl; a guanidinyl; -NRR, -NH-C(O)-R, -NH- C(O)-Ci-C4alk-NR ₂ , with R being independently H or a C1-C4 alkyl; a Ci-Cg alkyloxy optionally substituted by at least one halogen; and a heterocycloalkyl such as morpholinyl, pyrrolidonyl or pyrrolidinyl.

A could also be a phenyl, optionally substituted by one or several substituents selected from the group consisting of Co-C ₃ alkyl-C(0)-OR, Co-C ₃ alkyl-C(0)-R, with R being independently H or a C1-C4 alkyl optionally substituted by a group -NR'R' or OR', with R' being independently H or a Ci-C ₃ alkyl optionally substituted by at least one halogen.

In another particular aspect, the compound of formula (B) has

Ri is selected from the group consisting of a phenyl optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; a Ci-C ₃ alkyl optionally substituted by a halogen, preferably a methyl or an isopropyl; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a pyridinyl, preferably 2-pyridinyl or 3-pyridinyl, optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; a C1-C3 alkyl optionally substituted by a halogen, preferably a methyl or an isopropyl; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; an iodine, a chlorine, a fluorine or a bromine, preferably a chlorine or a fluorine, a morpholinyl optionally substituted by a C1-C3 alkyl optionally substituted by a halogen, a C1-C3 alkyloxy optionally substituted by a halogen and/or a halogen; a C3-C7 cycloalkyl, preferably a C ₅ -Cs cycloalky, more preferably a cyclohexyl, said cycloalkyl being optionally bridged and/or optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; a C1-C3 alkyl optionally substituted by a halogen, preferably a methyl or an isopropyl; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a piperidinyl optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; a C1-C3 alkyl optionally substituted by a halogen, preferably a methyl or an isopropyl; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by a halogen, in particular a fluorine or chorine, more preferably a fluorine; a C1-C3 alkyl optionally substituted by a halogen, preferably a methyl or an isopropyl; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; and an ethynyl (-CECH),

XI, X2 and X3 are selected in one of the following combinations: Xi, X2 and X3 are CH; Xi is CH and X2 and X3 are N; and Xi and X2 are CH and X3 is N;

-Y-L-B- is such that when A is a phenyl or a 5- or 6-membered heteroaryl, -Y-L-B- is selected in the group consisting of -S-CH ₂ -C(O)-NH-, -O-CH ₂ -C(O)-NH-, -O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH2-CH2- NH-S(O ₂ )-, -O-CH2-CH2-NH-, -O-CH ₂ -CH(CH ₂ -OH)-NH-C(O)-, -O-CH2-CH(CH ₂ -OCH ₃ )-NH- C(O)-, -O-CH ₂ -CH(CH ₃ )-NH-C(O)-, -O-CH(CH ₃ )-CH ₂ -NH-C(O)-, -NH-C(O)-NH-, -NH-CH2- CH2-NH-C(O)-, -O-cyclohexyl-NH-C(O)-, -NH-cyclohexyl-NH-C(O)-, -piperidinyl-NH- C(O)-, -O-tetrahydropyrimidyl-NH-C(O)- (e.g., -0-1,4,5,6-Tetrahydropyrimidinyl-NH- C(O)-), and -O-tetrahydropyrimidyl- (e.g., -O-1,4,5,6-Tetrahydropyrimidinyl-); preferably selected in the group consisting of -S-CH2-C(O)-NH-, -O-CH2-CH2-NH-C(O)-, -NH-C(O)-NH-, -O-cyclohexyl-NH-C(O)-, and -piperidinyl-NH-C(O)-; or when A is a 9-membered heteroaryl, -Y-L-B- is selected from the group consisting of - O-CH ₂ -CH ₂ -NH-C(O)-, -O-CH ₂ -CH ₂ -NH-, -O-CH2- and -S-CH ₂ -, preferably is -O-CH2- or - S-CH ₂ -;

A is selected from the group consisting of a phenyl; a phenyl substituted in para by a chlorine, a fluorine, a methyl, a morpholinyl, -CH ₂ -NH ₂ , -(CH ₂ ) ₂ -NH ₂ , -CH ₂ -N(CH3) ₂ , -CH ₂ -pyrrolidinyl, - CH ₂ -morpholinyl, -CH ₂ -guanidinyl, by -CH ₂ -C(O)-NH ₂ , -C(O)-NH ₂ , a methoxy, -CH ₂ -NH-C(O)-CH3, -CH ₂ -NH-C(O)-CH ₂ -NH ₂ , -CH ₂ -NH-C(O)-CH(iPr)-NH ₂ , -CH ₂ -NH-C(O)-CH ₂ -N(CH ₃ ) ₂ , nitro, -(CH ₂ ) ₂ - NH-C(O)-CH3; a phenyl substituted in para by a chlorine and in meta by a fluorine or a methoxy; a phenyl substituted in para by a chlorine and in ortho by a hydroxy, a cyano or a methyl; a phenyl substituted in meta by a chlorine; a 2-pyridinyl; a 2-pyridinyl substituted in para by a chlorine; a 3-pyridinyl; a 3-pyridinyl substituted in para by a chlorine; a 4-pyridinyl; a piperidinyl; a piperidinyl substituted by a methyl; a morpholinyl; a thiophenyl substituted by a halogen, preferably a chlorine; a thiophenyl substituted by a methyl; a benzoxazolyl substituted by a chlorine; a benzothiazolyl substituted by a chlorine; an indolyl substituted by a chlorine; a phthalimidyl and a thienopyridinyl; preferably selected from the group consisting of a phenyl, a phenyl substituted in para by a chlorine; a phenyl substituted in para by a chlorine and in meta by a fluorine, a methoxy, or a hydroxy; a phenyl substituted in para by a chlorine and in ortho by a hydroxy, a methoxy, a fluorine, or a methyl; a phenyl substituted in para by a fluorine, a methyl, a methoxy, -CH ₂ -NH-C(O)-CH3, -CH ₂ -CH ₂ -NH-C(O)-CH3,-CH ₂ -NH ₂ , - CH ₂ -morpholinyl, -CH ₂ -guanidinyl, -C(O)-NH ₂ , -CH ₂ -NH-C(O)-CH(iPr)-NH ₂ , a morpholinyl, or a nitro; a phenyl substituted in meta by a chlorine; a 2-pyridinyl substituted in para by a chlorine; a 3-pyridinyl substituted in para by a chlorine; a benzoxazolyl substituted by a chlorine; thiophenyl substituted by a chlorine; a benzothiophenyl substituted by a halogen, preferably a chlorine, an indolyl substituted by a chlorine; a benzothiazolyl substituted by a chlorine; and a phthalimidyl; and more preferably selected from the group consisting of a phenyl substituted in para by a chlorine, a phenyl substituted in para by a chlorine and in meta by a fluorine, a phenyl substituted in para by a chlorine and by a hydroxy in ortho, a phenyl substituted in para by -CH ₂ -NH-C(O)-CH3, a phenyl substituted in para by a nitro, a 2- pyridinyl substituted in para by a chlorine, and a thiophenyl substituted by a halogen, preferably a chlorine.

In a preferred aspect, the compound of formula (B) has one of the following formulae:

with Ri, Y and A as defined above in any one of the particular aspects, Z being O, NH or S, and n being an integer from 0 to 4, preferably being 1, and any pharmaceutical salt, stereoisomer, tautomer or solvate thereof.

In a particularly preferred aspect, the compound of formula (B) has one of the following formulae: with Ri, Y and A as defined above in any one of the particular aspects and any pharmaceutical salt, stereoisomer, tautomer thereof.

Preferably, in formulae (B-l), (B-2), (B-3), (B-3a) or (B-4), Ri is selected from the group consisting of a phenyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyridinyl, preferably 2-pyridinyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a pyrimidyl, preferably a 2-pyrimidyl, optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; or by a cyano; a morpholinyl optionally substituted by a C1-C3 alkyl optionally substituted by at least one halogen, by a C1-C3 alkyloxy optionally substituted by at least one halogen and/or by a halogen; a C3-C7 cycloalkyl, preferably a C ₅ -Cs cycloalkyl, more preferably a cyclohexyl, said cycloalkyl being optionally bridged and/or optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperidinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; a piperazinyl optionally substituted by at least one halogen, in particular a fluorine or chorine, more preferably a fluorine; by a C1-C3 alkyl optionally substituted by at least one halogen, preferably a methyl or an isopropyl; or by a C1-C3 alkyloxy optionally substituted by at least one halogen, preferably methoxy or isopropyloxy; an ethynyl (-CECH).

More preferably, in formulae (B-l), (B-2), (B-3), (B-3a) or (B-4), Ri is selected from the group consisting of a 2-pyridinyl, optionally substituted in ortho or para by a halogen, in particular a fluorine; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a phenyl, optionally substituted, preferably in para or ortho, by one or two halogens, in particular a fluorine, or by an alkyloxy, preferably a methyloxy or an isopropyloxy, more preferably an isopropyloxy; a pyrimidyl, preferably a 2-pyrimidyl, a morpholinyl; and a cyclohexyl.

Still more preferably, in formulae (B-l), (B-2), (B-3), (B-3a) or (B-4), Ri is selected from the group consisting of a 2-pyridinyl, optionally substituted in ortho or para by a halogen, in particular a fluorine; or a C1-C3 alkyloxy optionally substituted by a halogen, preferably methoxy or isopropyloxy; a phenyl, optionally substituted in para by a halogen, in particular a fluorine, or by an alkyloxy, preferably a methyloxy or an isopropyloxy, more preferably an isopropyloxy; a pyrimidyl, preferably a 2-pyrimidyl, a morpholinyl; and a cyclohexyl.

In a particular aspect of compounds of formulae (B-l), (B-3), (B-3a) or (B-4), A is a ring selected from optionally substituted a phenyl, a thiophenyl, a 2-pyridinyl, a 3-pyridinyl, a benzoxazolyl, a benzothiazolyl, a thiophenyl, a thienopyridinyl, an indolyl, an isoindolinonyl, a phthalimidyl and a benzothiophenyl, preferably a substituted phenyl, pyridinyl, benzoxazolyl and thiophenyl, the substitution of the ring A being selected from the group consisting of a halogen, optionally a chlorine, an iodine or a fluorine, preferably a fluorine or chlorine, more preferably a chlorine; a hydroxy, a cyano; a nitro; a Ci-Cg alkyl optionally substituted by at least one halogen; an amine; an amido; a nitro; a heterocycloalkyl such as morpholinyl; a guanidinyl; -NRR, -NH-C(O)-R, -NH-C(O)-Ci-C4alk-NR2, with R being independently H or a C1-C4 alkyl; a Ci-Cg alkyloxy optionally substituted by at least one halogen; and a heterocycloalkyl such as morpholinyl, or pyrrolidinyl or pyrrolidonyl.

A could also be a phenyl, optionally substituted by one or several substituents selected from the group consisting of Co-C3alkyl-C(0)-OR, Co-C3alkyl-C(0)-R, with R being independently H or a C1-C4 alkyl optionally substituted by a group -NR'R' or OR', with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen.

Preferably, in formulae (B-l), (B-3), (B-3a) or (B-4), A is selected from the group consisting of a phenyl; a phenyl substituted in para by a chlorine, a fluorine, a methyl, a morpholinyl, -CH2-NH2, -(Cbhh-NI-h, -CH ₂ -N(CH ₃ )2, -CH2-pyrrolidinyl, -CH2-morpholinyl, -CH2-guanidinyl, by -CH2-C(O)-NH2, -C(O)-NH2, a methoxy, -CH ₂ -NH-C(O)-CH ₃ , -CH2-NH-C(O)-CH ₂ -NH2, -CH2-NH-C(O)-CH(iPr)-NH2, -CH2-NH-C(O)-CH ₂ - N(CH ₃ )2, nitro, -(CH2)2-NH-C(O)-CH ₃ ; a phenyl substituted in para by a chlorine and in meta by a fluorine or a methoxy; a phenyl substituted in para by a chlorine and in ortho by a hydroxy, a cyano or a methyl; a phenyl substituted in meta by a chlorine; a 2-pyr idinyl; a 2-pyridinyl substituted in para by a chlorine; a 3-pyridinyl; a 3-pyridinyl substituted in para by a chlorine; a 4-pyridinyl; a piperidinyl; a piperidinyl substituted by a methyl; a morpholinyl; a thiophenyl substituted by a halogen, preferably a chlorine; and a thiophenyl substituted by a methyl.

More preferably, in formulae (B-l), (B-3), (B-3a) or (B-4), A is selected from the group consisting of a phenyl, a phenyl substituted in para by a chlorine; a phenyl substituted in para by a chlorine and in meta by a fluorine, a methoxy, or a hydroxy; a phenyl substituted in para by a chlorine and in ortho by a hydroxy, a methoxy, a fluorine, or a methyl; a phenyl substituted in para by a fluorine, a methyl, a methoxy, -CH ₂ -NH-C(O)-CH ₃ , -CH2-CH2-NH-C(O)-CH ₃ ,-CH ₂ -NH2, -CH ₂ -morpholinyl, -CH ₂ -guanidinyl, - C(O)-NH2, -CH2-NH-C(O)-CH(iPr)-NH2, a morpholinyl, or a nitro; a phenyl substituted in meta by a chlorine; a 2-pyridinyl substituted in para by a chlorine; a 3-pyridinyl substituted in para by a chlorine; and a thiophenyl substituted by a chlorine.

Still more preferably, in formulae (B-l), (B-3), (B-3a) or (B-4), A is selected from selected from the group consisting of a phenyl substituted in para by a chlorine, a phenyl substituted in para by a chlorine and in meta by a fluorine, a phenyl substituted in para by a chlorine and by a hydroxy in ortho, a phenyl substituted in para by -CH2-NH-C(O)-CH ₃ , a phenyl substituted in para by a nitro, a 2- pyridinyl substituted in para by a chlorine, and a thiophenyl substituted by a halogen, preferably a chlorine.

Preferably, the compounds of (B-2) has a 9-membered ring which is substituted by a halogen, preferably a chlorine.

In a particular aspect, the compound of formula (B) is selected from the compounds as shown in Tables 1, 2 and 3 and any pharmaceutical salt, stereoisomer, tautomer thereof.

Table 1

Table 2

In a particular aspect, the compound of the invention is as disclosed above and has an appetite suppressor effect as measured in the assay disclosed in the example section. Preferably, the food intake reduction in % compared to vehicle is of at least 10, 15, 20, 25, 30, 35, 40, 45 or 50%.

Compounds of formula (C) In a particular aspect of the present disclosure, the compound has the formula (C)

Cy-Y-L-B-A (C) and any pharmaceutical salt, stereoisomer, tautomer or a solvate thereof wherein

- Cy is a ring selected from the group consisting of with X4, X ₅ and Xg being independently N or CH; R2 being a Ci-Cg alkyl, linear, branched or cyclic, optionally substituted by a halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; R3, R4, Rs and Rg being independently selected from the group consisting of H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or by a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, and a C1-C3 alkoxy optionally substituted by at least one halogen or by a C1-C3 alkyloxy; with X ₇ , Xg, and Xg being independently N or CRb and at least one of X ₇ , Xg, and Xg is N, and X10 being CRb, with Rb being H or a C1-C3 alkyl optionally substituted by a halogen, a hydroxy, a C1-C3 alkyloxy, or a NR'R' with R' being H or a C1-C3 alkyl; R ₇ being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen or a C1-C3 alkyloxy; and with Xu being a heteroatom, preferably S, O or NRc with Rc being H or a Ci-Cg alkyl optionally substituted by at least one halogen, more preferably S, X12 being N or CH and X13 being CH or N; Rg being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen or a C1-C3 alkyloxy, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen or a C1-C3 alkyloxy;

- Y is present or absent and is selected from the group consisting of -S-, -NRd-, -O-, sulfinyl, sulfonyl, - C(O)-NRd-, and -C(O)-, with Rd being H or C1-C3 alkyl optionally substituted by at least one halogen; - L is present or absent and is selected from the group consisting of a linear C1-C4 alkylenyl, optionally comprising a double or triple bound, and optionally substituted by a C1-C3 alkyl, the C1-C3 alkyl being optionally substituted by a hydroxy, a methoxy, or a halogen, or by two substituents forming together a cycloalkyl or a heterocycloalkyl, a cycloalkyl, a heterocycloalkyl, an aryl and a heteroaryl, in particular a 5- or 6-membered cycloalkyl or heterocycloalkyl, especially a 5- or 6-membered heterocycloalkyl,

- B is present or absent and is selected from the group consisting of -NR _e -, -C(O)-NR _e -, -NR _e -C(O)-, - C(O)-, sulfinyl, sulfonyl, S(O)-NR _e -, -S(O2)-NR _e -, -NR _e -S(O)- and -NRe-SfCh)-, with R _e being H or a C1-C3 alkyl optionally substituted by at least one halogen,

- A is a ring selected from the group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and a 5-10- membered heteroaryl, said ring being optionally substituted by substitution(s) selected from the group consisting of a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyl optionally substituted by at least one halogen, a Ci-Cg alkyloxy optionally substituted by at least one halogen, a cycloalkyl, a heterocycloalkyl, an aryl, a heteroaryl, said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co- C ₃ alkyl-NH-C(O)-OR, C ₀ -C ₃ alkyl-NH-C(O)-NRR, C ₀ -C ₃ alkyl-C(O)-R, C ₀ -C ₃ alkyl-C(O)-OR, or C ₀ -C ₃ alkyl-NRR, with R being independently H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

In a more particular aspect of the present disclosure, the compound has the formula (C) Cy-Y-L-B-A (C) and any pharmaceutical salt, stereoisomer, tautomer or a solvate thereof wherein

- Cy is a ring selected from the group consisting of with X4, X ₅ and Xg being independently N or CH; R2 being a Ci-Cg alkyl, linear, branched or cyclic, optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; R3 being H or a C1-C3 alkyl optionally substituted by at least one halogen; and R4 being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; with X ₇ , Xg, and Xg being independently N or CR and at least one of X ₇ , Xg, and Xg is N, and X10 being CR, with R being H or a C1-C3 alkyl optionally substituted by a halogen, a hydroxy, a C1-C3 alkyloxy, or a NR'R' with R' being H or a C1-C3 alkyl; R ₇ being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen; with Xu being a heteroatom, preferably S, O or NH, more preferably S, and X12 being N or CH and X13 being CH or N; Rg being H, an aryl, a heteroaryl, a Ci-Cg alkyl optionally substituted by at least one halogen, a hydroxy, a cyano, an ethynyl (-CECH), an amino, or a C1-C3 alkoxy optionally substituted by at least one halogen;

- Y-L-B- is absent or selected from the group consisting of -S-CH2-C(O)-NH-, -S(O)-CH2-C(O)-NH-, -S(O2)- CH ₂ -, C(O)-NH-, -S-(CH ₂ ) ₃ - C(O)-NH-, -S-(CH ₂ )4-C(O)-NH-, -S-(CH ₂ ) ₂ -NH- C(O)-, -C(O)-piperazinyl-, - pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -S-CH2-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-CO-, -NH- CH ₂ -C(O)-NH-, -O-CH2-, -O-(CH ₂ ) ₂ -, -S-(CH ₂ ) ₃ -, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ )-C(O)-, - piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, -S-cyclohexyl-C(O)-NH-, -N(CH3)-CH2-C(O)-NH-, -C(O)-NH-, - CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₂ -C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, and - O-(CH ₂ )-C(O)-N(CH ₃ )-;

- A is a ring selected from the group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, a 5-10- membered heteroaryl, preferably a 9-membered heteroaryl, said ring being optionally substituted by substitution(s) selected from the group consisting of halogen, a cyano, hydroxy, an ethynyl (-CECH), nitro, amino, amido, a Ci-Cg alkyl optionally substituted by at least one halogen, an amino group, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl, said Ci-Cg alkyl, Ci-Cg alkyloxy, a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl being optionally substituted by a halogen, a cyano, a hydroxy, an ethynyl (-CECH), an amino group, a nitro, an amido, a guanidinyl, a Ci-Cg alkyloxy optionally substituted by at least one halogen, Co-C3alkyl-NH-C(0)-R, Co-Csalkyl-NH- C(O)-OR, Co-C3alkyl-NH-C(0)- NRR, Co-C3alkyl-C(0)-R, Co-C3alkyl-C(0)-OR, or Co-Csalkyl-NRR, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, by a guanidinyl, or by a group -NR'R', -OR', -C(O)-NR'R', -C(O)-OR', -SR' or combination thereof, with R' being independently H or a C1-C3 alkyl optionally substituted by at least one halogen, and wherein, when A is a ring substituted by a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, the ring can be fused to the cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

Accordingly, the compound of the formula (C) may have one of the formulae (C-l), (C-2) and (C-3) and any pharmaceutical salt, stereoisomer, tautomer or a solvate thereof with Xs, Rs, Y, L, B and A being as defined above.

Compound of (C-l)

In a particular aspect, the compound of formula (C) has a formula (C-l) and X4, X ₅ and Xg are independently N or CH; R2 is selected from the group consisting of a methyl, an ethyl, a n-propyl, an isopropyl, a n-butyl, an isobutyl, a tertbutyl, optionally substituted by at least one halogen, preferably a fluorine, or a methoxy; R3 is H or a methyl optionally substituted by a halogen, preferably a fluorine; R4 being H or a fluorine, R ₅ and Rg are H; and

-Y-L-B- is absent or selected from the group consisting of selected from the group consisting of -S-CH ₂ -C(O)-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -, C(O)-NH-, -S-(CH ₂ ) ₃ - C(O)-NH-, -S-(CH ₂ ) ₄ - C(O)-NH-, -S-(CH ₂ ) ₂ -NH- C(O)-, -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, - S-CH ₂ -, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-CO-, -NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O- (CH2)3-C(O)-NH-, -S-(CH2)-C(0)-, - piperazinyl-C(O)-, -0-2-oxo-pyrrolidinyl-, -S-cyclohexyl-C(O)- NH-, -N(CH ₃ )-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH-CH ₂ -C(O)- NH-, -S-(CH ₂ ) ₂ -C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, and -O-(CH ₂ )-C(O)-N(CH ₃ )-; preferably selected from the group consisting of -S-CH ₂ -C(O)-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -S- (CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH-, -S-(CH ₂ ) ₂ -NH-C(O)-, -C(O)-piperazinyl-, -pyrrolidinyl-C(O)- NH-, -S-piperidinyl-C(O)-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)-NH-, -O- (CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ )-C(O)-, -piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, - S-cyclohexyl-C(O)-NH-, -NMe-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)- and -O-piperidinyl-C(O)- ; more preferably selected from the group consisting of -S-CH2-C(O)-NH-, -S(O)-CH2-C(O)-NH-, -S(O ₂ )-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH-, -S-(CH ₂ ) ₂ -NH-CO-, -C(O)- piperazinyl-, -pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -O-(CH2)2-NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )- C(O)-, -NH-CH2-C(O)-NH-, and -O-piperidinyl-C(O)- , and

A is a ring selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para, a phenyl substituted in para by a Co-C ₃ alkyl-NH-C(0)-R, with R being H or a Ci-C ₄ alkyl optionally substituted by at least one halogen, a morpholinyl, a piperazinyl or a piperidinyl optionally substituted by a methyl, and a cyclohexyl; or

-Y-L-B- is absent or selected from the group consisting of -O-CH2-, -S-CH2-, and -S-(CH2) ₃ - and A is benzoxazolyl, benzothiazolyl, thienopyridinyl, benzothiophenyl, or indolyl, preferably benzoxazolyl or benzothiazolyl, preferably substituted by a halogen, in particular a chlorine, preferably in position 6.

In another particular aspect, the compound of formula (C) has a formula (C-l) and X ₄ , X ₅ and Xg are independently N or CH; R2 is selected from the group consisting of a methyl, an ethyl, a n-propyl, an isopropyl, a n-butyl, an isobutyl, a tertbutyl, optionally substituted by at least one halogen, preferably a fluorine, or a methoxy; R ₃ is H or a methyl optionally substituted by a halogen, preferably a fluorine; R ₄ being H or a fluorine, R ₅ and Rg are H; and

-Y-L-B- is absent or selected from the group consisting of selected from the group consisting of - C(O)-NH-, -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )- CO-, -NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, - piperazinyl-C(O)-, -0-2-oxo- pyrrolidinyl-, -N(CH ₃ )-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH- CH2-C(O)-NH-, -O-(CH2) ₃ -C(O)-NH-, and -O-(CH2)-C(O)-N(CH ₃ )-; preferably selected from the group consisting of -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O-(CH2)2-NH-C(O)-, -O-(CH ₂ ) ₂ - N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -piperazinyl-C(O)-, - 0-2-oxo-pyrrolidinyl-, -NMe-CH2-C(O)-NH-, -C(O)-NH-, -CH2-NH-C(O)- and -O-piperidinyl-C(O)- ; more preferably selected from the group consisting of -C(O)-piperazinyl-, -pyrrolidinyl-C(O)- NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)-NH-, and -O-piperidinyl-C(O)- , and

A is a ring selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para, a phenyl substituted in para by a Co-C ₃ alkyl-NH-C(0)-R, with R being H or a C1-C4 alkyl optionally substituted by at least one halogen, a morpholinyl, a piperazinyl or a piperidinyl optionally substituted by a methyl, and a cyclohexyl; or

-Y-L-B- is absent or selected from the group consisting of -O-CH ₂ -, -S-CH ₂ -, and -S-(CH ₂ )3- and A is a benzoxazolyl or a benzothiazolyl substituted by a chlorine, preferably in position 6.

In a more particular aspect, when Cy is

R ₂ is a methyl, ethyl or propyl, optionally substituted by a methoxy or at least one halogen;

R3 and R ₅ are H;

R4 is H or a halogen, preferably a fluorine; and

Re is H, CH3, or CF3.

In a very particular aspect, when Cy is

X4, X ₅ and Xg are N, or X4, X ₅ and Xg are CH,

R ₂ is a methyl, ethyl or propyl optionally substituted by a methoxy, and

R3 and R4 are H.

In a more particular aspect, when A is a ring selected from the group consisting of a 6-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, -Y-L-B- is absent or selected from the group consisting of selected from the group consisting of -S-CH ₂ -C(O)-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )-CH ₂ -, C(O)-NH-, - S-(CH ₂ ) ₃ - C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH-, -S-(CH ₂ ) ₂ -NH- C(O)-, -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, - S-piperidinyl-C(O)-, -S-CH ₂ -, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-CO-, -NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )- C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ )-C(O)-, - piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, -S-cyclohexyl- C(O)-NH-, -N(CH ₃ )-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₂ -C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, and -O-(CH ₂ )-C(O)-N(CH ₃ )-.

Preferably, -Y-L-B- is selected from the group consisting of -S-CH ₂ -C(O)-NH-, -S(O)-CH ₂ -C(O)-NH-, -S(O ₂ )- CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH-, -S-(CH ₂ ) ₂ -NH-C(O)-, -C(O)-piperazinyl-, - pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)- NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ )-C(O)-, -piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, - S-cyclohexyl-C(O)-NH-, -NMe-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)- and -O-piperidinyl-C(O)-.

More preferably, -Y-L-B- is selected from the group consisting of -S-CH ₂ -C(O)-NH-, -S(O)-CH ₂ -C(O)-NH- , -S(O ₂ )-CH ₂ -C(O)-NH-, -S-(CH ₂ ) ₃ -C(O)-NH-, -S-(CH ₂ ) ₄ -C(O)-NH-, -S-(CH ₂ ) ₂ -NH-CO-, -C(O)-piperazinyl-, - pyrrolidinyl-C(O)-NH-, -S-piperidinyl-C(O)-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)- NH-, and -O-piperidinyl-C(O)- .

Optionally, -Y-L-B- is selected in one of the following groups:

-Y-L-B- is absent or selected from the group consisting of selected from the group consisting of C(O)-NH-, -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O-(CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )- CO-, -NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, - piperazinyl-C(O)-, -O-2-oxo- pyrrolidinyl-, -N(CH ₃ )-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH-C(O)-, -(CH ₂ ) ₂ -C(O)-NH-, -C(O)-NH- CH ₂ -C(O)-NH-, -O-(CH ₂ ) ₃ -C(O)-NH-, and -O-(CH ₂ )-C(O)-N(CH ₃ )-;

-Y-L-B- is selected from the group consisting of -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O- (CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)-NH-, -O-(CH ₂ )-C(O)-NH-, -O-(CH ₂ ) ₃ - C(O)-NH-, -piperazinyl-C(O)-, -O-2-oxo-pyrrolidinyl-, -NMe-CH ₂ -C(O)-NH-, -C(O)-NH-, -CH ₂ -NH- C(O)- and -O-piperidinyl-C(O)-; or

-Y-L-B- is selected from the group consisting of -C(O)-piperazinyl-, -pyrrolidinyl-C(O)-NH-, -O- (CH ₂ ) ₂ -NH-C(O)-, -O-(CH ₂ ) ₂ -N(CH ₃ )-C(O)-, -NH-CH ₂ -C(O)-NH-, and -O-piperidinyl-C(O)- .

In a more particular aspect, when A is a 9-membered heteroaryl, -Y-L-B- is absent or selected from the group consisting of -O-CH ₂ -, -S-CH ₂ -, and -S-(CH ₂ ) ₃ -.

In a particular aspect, A is a ring selected from the group consisting of a 6-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. A can be a ring selected from the group consisting of a phenyl, a morpholinyl, a piperazinyl, a piperidinyl and a cyclohexyl, said ring being optionally substituted.

In a more particular aspect, A is a ring selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a methyl, an iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl or -CH ₂ -NH-C(O)-CH ₃ in para, a morpholinyl, a piperazinyl or a piperidinyl optionally substituted by a methyl, and a cyclohexyl.

In a very specific aspect, A is a ring selected from the group consisting of a phenyl substituted by a chlorine in para and optionally further substituted in ortho by a group selected from an iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para, and a cyclohexyl.

In a particular aspect, A is a 9-membered heteroaryl. Preferably, A is a substituted 9-membered heteroaryl, preferably by a halogen, more preferably a chlorine.

In a particular aspect, when A is a 9-membered heteroaryl, A is benzoxazolyl, benzothiazolyl, thienopyridinyl, benzothiophenyl, or indolyl, preferably substituted by a halogen, more preferably a chlorine, preferably in position 6. Preferably, A is benzoxazolyl or benzothiazolyl, preferably substituted by a halogen, more preferably a chlorine, preferably in position 6.

Compound of (C-2)

In a particular aspect, the compound of formula (C) has a formula (C-2) and one of X ₇ and X ₈ is N and the other is CH, Xg is CH or N and Xio is CRb, with Rb being H or a C1-C3 alkyl optionally substituted by a halogen, a hydroxy, a C1-C3 alkyloxy, or a NR'R' with R' being independently H or a C1-C3 alkyl; R ₇ is H; -Y-L-B- is selected from the group consisting of -O-CH2-, -O-(CH2h-NH-C(O)-, -S-(CH2)2-NH-CO-, -O- (CH2)2-N(CH3)-C(O)-, -O-CH2-C(O)-NH-, and -S-CH2-C(O)-NH-, preferably selected from the group consisting of -O-CH ₂ -, -O-(CH ₂ ) ₂ -NH-C(O)-, and -S-(CH ₂ ) ₂ -NH-C(O)-; and

A is a ring selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para which is optionally substituted by an a C2-C3 acyl, a morpholinyl, a piperazinyl or a piperidinyl optionally substituted by a methyl, a cyclohexyl and a benzoxazolyl or a benzothiazolyl substituted by a chlorine, preferably in position 6, preferably selected from the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para optionally substituted by an a C2-C3 acyl.

In a more particular aspect, when Cy is X ₇ , Xg, and Xio are CH and Xg is N; or Xg, Xg, and Xio are CH and X ₇ is N; or X ₇ , Xg, Xg, and Xio are

CH;

- R ₇ is H.

In a very particular aspect, when Cy is

X ₇ , Xg, and Xio are CH and Xg is N; or Xg, Xg, and Xio are CH and X ₇ is N;

- R ₇ is H.

In a particular aspect, -Y-L-B- is selected from the group consisting of -O-CH2-, -O-(CH2h-NH-C(O)-, -S- (CH ₂ ) ₂ -NH-CO-, -O-(CH ₂ )2-N(CH ₃ )-C(O)-, -O-CH ₂ -C(O)-NH-, and -S-CH ₂ -C(O)-NH-, preferably selected from the group consisting of -O-CH2-, -O-(CH2)2-NH-C(O)-, and -S-(CH2)2-NH-C(O)-.

In a particular aspect, A is a ring selected from the group consisting of a 6-membered aryl or heteroaryl substituted by a chlorine in para; and a 9-membered heteroaryl substituted by a chlorine, preferably in position 5 or 6.

In a very specific aspect, A is a ring selected from the group consisting of a phenyl substituted by a chlorine in para; and a benzoxazolyl substituted by a chlorine, preferably in position 5 or 6.

Compound of (C-3)

In a particular aspect, the compound of formula (C) has a formula (C-3) and Xu is S, O or NH, X12 and X13 are independently N or CH; Rg is H, a phenyl or a pyridinyl, in particular a 2-pyridinyl;

-Y-L-B- is absent or selected from the group consisting of -C(O)-NH-, and -CH2-NH-C(O)-; and

A is selected in the group consisting of a phenyl optionally substituted by a chlorine in para and optionally further substituted in ortho by a group selected from a iodine, an ethynyl (-CECH), and a cyano, a phenyl substituted by an aminomethyl in para which is optionally substituted by an a C2-C3 acyl, and a benzoxazolyl substituted by a chlorine, preferably in position 6.

In a very particular aspect, when Cy is

Xu is S, X12 and X13 are CH, and Rg is H, a phenyl or a pyridinyl.

-Y-L-B- is absent or selected from the group consisting of -C(O)-NH-, and -CH2-NH-C(O)-.

A is a ring selected in the group consisting of a phenyl optionally substituted by a chlorine in para, and a benzoxazolyl substituted by a chlorine, preferably in position 6. In a particular aspect, the compound of formula (C) is selected from the compounds as shown in Tables

4, 5 and 6 and any salt, stereoisomer, tautomer or solvate thereof.

Table 4

Table 5

Table 6

In a particular aspect, the compound of formula (C) is selected from the compounds as shown in Tables

7, 8 and 9 and any salt, stereoisomer, tautomer or solvate thereof.

Table 7

Table 8

In a particular aspect, the compound of the invention is as disclosed above and has an appetite suppressor effect as measured in the assay disclosed in the example section. Preferably, the food intake reduction in % compared to vehicle is of at least 10, 15, 20, 25, 30, 35, 40, 45 or 50%.

Pharmaceutical or veterinary compositions and the uses thereof

As illustrated by examples, the inventors have demonstrated the therapeutic interest of the new compounds of the invention. Accordingly, the present invention relates to a pharmaceutical or veterinary composition comprising any new compound according to the present invention. Preferably, the pharmaceutical or veterinary composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient. The present invention relates to the use of any new compound according to the invention as a drug or as a medicine. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of any new compound according to the invention, is administered to said subject in need thereof. The invention also relates to the use of any new compound according to the invention, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising any new compound according to the invention for use as a drug.

More particularly, the present invention provides compounds having an appetite-suppressor effect as shown by their capacity to reduce the food intake. Beneficial or desired clinical results from the compound of the present invention, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, include, without limitation, reduced body weight, decreased weight-gain, reduced appetite, weight loss, management of weight, suppression of an appetite for food, controlled food intake, reduced or stabilized body fat content, reduced or stabilized blood or serum glucose and blood or serum insulin levels, amelioration, palliation, stabilization, diminishment of extent of obesity- related diseases, or a delay or slowing of obesity related disease progression. By treatment is meant inhibiting or reducing an increase in obesity-related symptoms (e.g. weight gain) when compared to the absence of treatment, and is not necessarily meant to imply complete cessation of the relevant condition.

Therefore, the compounds of the present invention are of interest as appetite suppressant. Accordingly, the present invention relates to any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for use as appetite suppressant. The present invention relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it as appetite suppressant. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it is administered to said subject in need thereof. The invention also relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for the manufacture of a medicine for use as appetite suppressant.

The present invention also relates to any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for use for the treatment of a metabolic disease, an eating disorder, a syndrome or a medication-induced weight gain. The present invention relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for the treatment of a metabolic disease, an eating disorder, a syndrome or a medication-induced weight gain. The invention further relates to a method for treating a metabolic disease, an eating disorder, a syndrome or a medication-induced weight gain in a subject, wherein a therapeutically effective amount of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it is administered to said subject in need thereof. The invention also relates to the use of any compound according to the present invention or a pharmaceutical or veterinary composition comprising it for the manufacture of a medicine for the treatment of a metabolic disease, an eating disorder, a syndrome or a medication-induced weight gain. The metabolic disease can be selected from the non-exhaustive list comprising obesity, diabetes (type 1 or type 2 diabetes), hypertension, non-alcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD), insulin resistance, coronary heart disease, cardiovascular diseases (such as congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, or peripheral artery disease), and dyslipidemia.

The eating disorders can be selected from the non-exhaustive list comprising bulimia nervosa, binge eating disorder, night eating syndrome, compulsive overeating, anxiety, depression, Gourmand syndrome, Prader-Willi syndrome.

The syndromes can be selected from metabolic syndrome, Cohen syndrome, Bardet-Biedl syndrome, polycystic ovary syndrome and MOMO syndrome.

The subject to be treated may have a disorder that leads to weight gain through excessive consumption of food, such as a disorder selected from binge eating disorder, subclinical binge eating, Prader-Willi syndrome and metabolic syndrome (also known as syndrome X or insulin-resistance syndrome). The subject may have other excess weight-related metabolic disorders. Examples of these include insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, type 2 diabetes, hypertension, dyslipidemia (or a combination of these metabolic risk factors), glucagonomas, stroke, respiratory dysfunction, or renal disease.

Body mass index (BMI) is a simple index of weight-for-height that is commonly used for human adults to assess whether a patient is "overweight" or "obese". It is defined as an individual's weight in kilograms divided by the square of his or her height in meters (kg/m2). The most commonly used definitions, established by the World Health Organization (WHO) in 1997 and published in 2000, provide the following classifications based on BMI: overweight = human adult with BMI of between about 25 to about 29.99 kg/m2; class I obesity = a human adult with BMI from between about 30 kg/m2 to about 34.99 kg/m2; severe obesity (class II obesity) = a human adult with BMI of between about 35 kg/m2 to about 39.99 kg/m2; morbid obesity (class III obesity) = a human adult with BMI of between about 40 kg/m2 and 44.99 kg/m2. Some physicians/clinicians/surgeons may also refer to super obesity, being a BMI of greater than about 45 kg/m2 in a human adult subject.

In addition, the compounds of the present invention are also of interest in order to promote weight loss in a subject. Then, the invention may relate to a method for promoting weight loss or preventing weight gain comprising administering a compound of the present invention or a composition comprising it to the subject. In a particular embodiment, the subject can be obese. In this context, for human being, the Body Mass Index (BMI) is higher or equal to 30. In an alternative embodiment, the subject can be overweight. The overweight can be only minor, e.g. unsightly but without any threat to the health. In this context, the Body Mass Index (BMI) is lower than 30. In this aspect, the method is a non-therapeutic method. For instance, the goal could be improved the physical appearance by reducing the weight. The subject may have a normal body mass index (up to 25).

The compound according to the invention or the pharmaceutical composition according to the invention may be administered by any conventional route of administration. In particular, the compound or the pharmaceutical composition of the invention can be administered by a topical, enteral, oral, parenteral, intranasal, intravenous, intraperitoneal, intra-arterial, intramuscular, intratumoral, subcutaneous or intraocular administration and the like. In particular, the compound according to the invention or the pharmaceutical composition according to the invention can be formulated for a topical, enteral, oral, parenteral, intranasal, intravenous, intraperitoneal, intraarterial, intramuscular, intratumoral, subcutaneous or intraocular administration and the like.

Preferably, the compound according to the invention or the pharmaceutical composition according to the invention is administered by enteral or parenteral route of administration. When administered parenterally, the compound according to the invention or the pharmaceutical composition according to the invention is preferably administered by intravenous or intraperitoneal route of administration. When administered enterally, the compound according to the invention or the pharmaceutical composition according to the invention is preferably administered by oral route of administration.

The pharmaceutical composition comprising the molecule is formulated in accordance with standard pharmaceutical practice (Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York) known by a person skilled in the art.

For oral administration, the composition can be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules and liquid preparations such as syrups, elixirs, and concentrated drops. Nontoxic solid carriers or diluents may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. For compressed tablets, binders, which are agents which impart cohesive qualities to powdered materials, are also necessary. For example, starch, gelatine, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders. Disintegrants are also necessary in the tablets to facilitate break-up of the tablet. Disintegrants include starches, clays, celluloses, algins, gums and crosslinked polymers. Moreover, lubricants and glidants are also included in the tablets to prevent adhesion to the tablet material to surfaces in the manufacturing process and to improve the flow characteristics of the powder material during manufacture. Colloidal silicon dioxide is most commonly used as a glidant and compounds such as talc or stearic acids are most commonly used as lubricants.

For transdermal administration, the composition can be formulated into ointment, cream or gel form and appropriate penetrants or detergents could be used to facilitate permeation, such as dimethyl sulfoxide, dimethyl acetamide and dimethylformamide.

For transmucosal administration, nasal sprays, rectal or vaginal suppositories can be used. The active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate.

Pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.

The compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses. Preferably, the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day. The treatment may last as long as the disease persists.

The amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient.

In a preferred embodiment, the total compound dose for each administration of the compound according to the invention or of the pharmaceutical composition according to the invention is comprised between 0.00001 and 1 g.

The form of the pharmaceutical compositions, the route of administration and the dose of administration of the compound according to the invention, or the pharmaceutical composition according to the invention can be adjusted by the man skilled in the art according to the type and severity of the disease, and to the patient, in particular its age, weight, sex, and general physical condition.

The present invention also relates to the combined use of a compound of the present invention with at least another active ingredient or with an appropriate dietary regimen.

Further aspects and advantages of the present invention will be described in the following examples, which should be regarded as illustrative and not limiting.

EXAMPLES

SYNTHESIS

General synthesis of 2-chloro-5-(het)arylpyrimidine

2-chloro-5-phenylpyrimidine is commercially available. 2-Chloro-5-(pyrid-2-yl)pyrimidine was prepared by Negishi cross-coupling according to a known procedure (Organic Process Research & Development 2007, 11, 237-240). The same procedure was followed for pyridyls with additional substituents.

General Synthesis of 2-N- and 2-O-substituted 5-(het)arylpyrimidines

Route Rl: , ₂

Route Rl: Synthesis exemplified on compound 60

Compound 60

2-Chloro-5-(pyrid-2-yl)pyrimidine was prepared by Negishi cross-coupling according to a known procedure (Organic Process Research & Development 2007, 11, 237-240). The same procedure was followed for pyridyls with additional substituents. 4-Chloro-N-(2-hydroxyethyl)benzamide was prepared as previously described from 4-chlorobenzoyl chloride and 2-aminoethanol in DCM.

4-Chloro-N-(2-hydroxyethyl)benzamide (521 mg, 2.73 mmol) was dissolved in anhydrous THF (25 mL). The solution was cooled to 0°C, and 60% NaH on mineral oil (115 mg, 3.00 mmol) was added. After 15 min 2-chloro-5-(pyrid-2-yl)pyrimidine (500 mg, 2.73 mmol) was added. The resulting mixture was stirred at room temperature under argon for 16h. The mixture was poured into H2O (350 mL). Precipitate was filtered and recrystallized from EtOH/HjO to yield white solid (511 mg, 55%). ¹ H-NMR (300 MHz, CDCk) 6: 9.11 (s, 2H), 8.76-8.66 (m, 1H), 7.85-7.62 (m, 4H), 7.44-7.35 (m, 2H), 7.34-7.25 (m, 1H), 6.92-6.80 (m, 1H), 4.64 (t, 7=4.9 Hz, 2H); 3.98-3.89 (m, 2H). UPLC-ESI (m/z): 355, 357 [M+H] ⁺ .

Route Rl: In an additional example of route Rl, the amide coupling is performed after Boc- deprotection, synthesis exemplified on compound 118

Compound 118-PF6 In a variation of the general route Rl, the following preparation exemplifies the late introduction of amides.

To solution of tert-butyl (2-hydroxyethyl)carbamate (1.94 mL 12.5 mmol) in THF (10 mL), NaH (60 % in mineral oil, 542 mg, 13.6 mmol) was added at 0 °C. After stirring for 20 min at the same temperature, 2-chloro-5-(pyridin-2-yl)pyrimidine (1, 2.00 g, 10.4 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. Sat. NH4CI solution (20 mL) was added and the mixture was extracted with EtOAc (2x100 mL). The combined EtOAc extracts were washed with brine (100 mL), dried over NajSC and evaporated. Purification of the residue by column chromatography (eluent DCM/acetone) yielded 01 as slightly yellow powder (2.38 g, 72%). ¹ H-NMR 300 MHz, CDCI3 6 (ppm): 9.11 (s, 2H), 8.70 (ddd, 7=4.8, 1.7, 0.9 Hz, 1H), 7.79 (dt, 7=7.8, 1.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.29 (ddd, 7=7.8, 4.8, 0.9 Hz, 1H), 5.17-5.00 (m, 1H), 4.55-4.45 (m, 2H), 3.65-3.52 (m, 2H), 1.44 (s, 9H). ESI (m/z): 317 [M+H] ⁺ .

To solution of 01 (2.38 g 7.52 mmol) in DCM (15 ml), TFA (3 mL) was added. The reaction mixture was stirred at room temperature for 1 h and then evaporated. MeOH (20 mL) and HCI (5M in iPrOH, 12 mL) was added to the residue and the mixture was stirred at room temperature for 3 h. EtjO (150 mL) was added. Filtration and washing of precipitates with EtjO (2x150 mL) yielded 02 as white powder (1.89 g, 99%). ^X H-NMR 300 MHz, DMSO-dg 6 (ppm): 9.29 (s, 2H), 8.72 (ddd, 7=4.9, 1.7, 0.9 Hz, 1H), 8.36-8.12 (br s, 2H), 8.13-8.06 (m, 1H), 8.00 (dt, 7=7.6, 1.7 Hz, 1H), 7.48 (ddd, 7=7.6, 4.9, 0.9 Hz, 1H), 7.02-6.21 (m, 3H), 4.63-4.54 (m, 2H), 3.34-3.20 (m, 2H). ESI (m/z): 217 [M+H] ⁺ .

To suspension of l-methylpiperidine-4-carboxylic acid (5) (283 mg 1.98 mmol), 02 (500 mg 1.98 mmol) and HATU (752 mg 1.98 mL) in DMF (15 mL) was added diisopropylethylamine (1.03 mL 5.94 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with NaHCOs (50 ml) and diluted with DCM (50 mL). The aqueous layer was separated, extracted with DCM (50 mL), the organic layers combined, washed with water (2x50 mL) and brine (50 mL), dried over Na2SO4 and evaporated. Recrystallization of the residue from EtOH yielded compound 118-PF6 as yellow solid (200 mg, 21%). ^X H-NMR 300 MHz, DMSO-dg 6 (ppm): 9.25 (s, 2H), 9.16-9.00 (m, 1H), 8.69 (ddd, J=4.8, 1.8, 1.0 Hz, 1H), 8.27 (t, J= 5.5 Hz, 1H), 8.05 (dt, J=8.0, 1.0 Hz, 1H), 7.97-7.90 (m, 1H), 7.42 (ddd, J=7.5, 4.8, 1.1 Hz, 1H), 4.41 (t, J= 5.5 Hz, 2H), 3.53-3.46 (m, 2H), 3.46-3.36 (m, 2H), 3.05-2.80 (m, 2H), 2.75 (s, 3H), 2.44-2.32 (m, 1H), 1.98-1.64 (m, 4H). ESI (m/z): 342 [M-PF ₆ ] ⁺ . The free base was obtained by column chromatography (eluent EtOH, then EtOH + 0.7% TEA) to afford compound 118 as yellow solid (280 mg, 41%). ^X H-NMR 300 MHz, DMSO-dg 6 (ppm): 9.23 (s, 2H), 8.69 (ddd, J=4.8, 1.8, 1.0 Hz, 1H), 8.07-7.99 (m, 2H), 7.93 (dt, J=7.7, 1.8 Hz, 1H), 7.41 (ddd, J=7.5, 4.8, 1.0 Hz, 1H), 4.38 (t, J=5.7, 2H), 3.48-3.43 (m, 2H), 3.76-3.70 (m, 2H), 2.10 (s, 3H), 2.08-2.00 (m, 1H), 1.78 (dt, J=11.5, 3.1 Hz, 2H), 1.63-1.48 (m, 4H). ESI (m/z): 342 [M+H] ⁺ . Route R2: Synthesis exemplified on compound 125

Intermediate QI

To solution of N-(2-hydroxyethyl)-4-chlorobenzamide (1.00 g, 5.01 mmol) in anhydrous THF (40 mL), NaH (60% in mineral oil, 220 mg, 5.51 mmol) was added at 0 °C (ice bath). The resulting suspension was stirred at 0 °C for 20 min. 2-Chloro-5-iodopyrimidine (1.20 g, 5.01 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The suspension was poured into water (150 mL). Precipitates were filtered, dissolved in EtOH and the solution was evaporated to afford 4 as beige solid (1.89 g, 94 %). ^X H-NMR 300 MHz, CDCI3 6 (ppm): 8.68 (s, 2H), 7.78-7.68 (m, 2H), 7.47-7.38 (m, 2H), 6.74-6.60 (m, 1H), 4.58-4.52 (m, 2H), 3.97-3.86 (m, 2H). ESI (m/z): 404 [M+H]+.

Compound 125

A mixture of the above prepared Q2 (600 mg, 1.49 mmol), 2-fluorophenylboronic acid (312 mg, 2.23 mmol), Pd(OAc)2 (3.0 mg, 0.015 mmol) and K3PO4 (631 mg, 2.97 mmol) in ethylene glycol (10 mL) was stirred at 80 °C for 3 h. After cooling to room temperature, brine (100 mL) and EtOAc (150 mL) were added, the organic layer was separated, dried over NajSCU and evaporated. Purification of the residue by column chromatography (eluent DCM/acetone 5/1) yielded the title compound as white powder (500 mg, 90 %). ^X H-NMR 300 MHz, CDCI3 6 (ppm): 8.74 (d, J=1.4 Hz, 2H), 7.79-7.73 (m, 2H), 7.48-7.38 (m, 4H), 7.33-7.29 (m, 1H), 7.28-7.19 (m, 1H), 6.86-6.70 (m, 1H), 4.69-4.63 (m, 2H), 4.00-3.93 (m, 2H). ESI (m/z): 372 [M+H]+.

In a similar manner, the following compounds were prepared with the appropriate starting materials.

Synthesis of Compound 62 and general amide methylation to Compound 621:

Compound 62 4-Phenylphenol (3.00 g, 17.6 mmol) was dissolved in acetone (100 mL). K2CO3 (4.87 g, 35.3 mmol) and bromoacetonitrile (1.42 mL, 21.2 mmol) were added. The reaction mixture was stirred at room temperature for 20 h before it was concentrated in vacuo. To the crude was added H2O, the resulting mixture was extracted with EtOAc (3x35mL). The combined organic layers were washed with brine and H2O, dried over Na2SO4, and evaporated. The crude was purified by column chromatography on silica gel, eluent EtOAc/petrol ether 1:6 to yield a white solid (3.65 g, 99%). ¹ H NMR (300 MHz, CDCI3) 6: 7.61-7.55 (m, 4H), 7.47-7.42 (m, 2H), 7.38-7.32 (m, 1H), 7.06 (d, 7=8.7 Hz, 2H), 4.79 (s, 2H). UPLC-ESI (m/z): 210 [M+H] ⁺ .

IJAIH4 (1.32 g, 34.9 mmol) was suspended in Et20 (50 mL). The suspension was cooled to 0 °C. To the suspension was added a solution of the above prepared 2-([l,l'-biphenyl]-4-yloxy)acetonitrile (3.65 g, 17.4 mmol) in Et20 (100 mL). The resulting mixture was stirred at 0 °C for 1 h, then at room temperature for 20 h. The reaction mixture was cooled to 0 °C and H2O was added carefully. After 15 min, EtOAc (150 mL) was added. The organic layer was separated, washed with H2O and brine, dried over Na2SO4 and evaporated to yield a light brown solid (3.00 g, 81%). ¹ H NMR (300 MHz, CDCI3) 6: 7.48-7.41 (m, 4H), 7.35-7.30 (m, 2H), 7.24-7.17 (m, 1H), 6.89 (d, 7=8.7 Hz, 2H), 3.94 (t, 7=5.1 Hz, 2H), 3.02 (br s, 2H). UPLC-ESI (m/z): 214 [M+H] ⁺ .

The above prepared 2-([l,l'-Biphenyl]-4-yloxy)ethan-l-amine (3.00 g, 14.06 mmol) and 4- chlorobenzoyl chloride (2.86 mL, 22.5 mmol) were suspended in anhydrous CH2CI2 (100 mL). To the suspension was added NEt3 (3.92 mL, 28.1 mmol). The resulting yellow solution was stirred at room temperature under argon for 16 h. The orange solution was diluted with H2O (100 mL). The resulting mixture was extracted with CH2CI2 (3x100 mL), dried over Na2SC>4 and evaporated. The crude was purified by column chromatography on silica gel, eluent CH2CI2. After concentration of the productcontaining fractions, the residue was washed with hot Et20 to yield the title compound as a white solid (1.95 g, 39 %). R _f =0.21 (CH2CI2). ^X H NMR (300 MHz, CDCI3) 6: 7.77-7.69 (m, 2H), 7.58-7.50 (m, 4H), 7.46- 7.37 (m, 4H), 7.35-7.28 (m, 1H), 7.03-6.96 (m, 2H), 6.62-6.51 (m, 1H), 4.20 (t, 7=5.0 Hz, 2H), 3.94-3.86 (m, 2H). UPLC-ESI (m/z): 352, 354 [M+H] ⁺ .

Compound 621

Compound 62 (500 mg, 1.42 mmol) was dissolved in anhydrous THF (15 mL). The solution was cooled to 0 °C, and 60% NaH in mineral oil (114 mg, 2.84 mmol) was added. The resulting suspension was stirred at 0 °C under argon for 20 min. To the suspension was added Mel (0.22 mL, 3.55 mmol). The resulting suspension was stirred at room temperature under argon for 16 h. The reaction was quenched with H2O (10 mL) and extracted with CH2CI2 (3x15 mL). The organic layer was dried over Na2SC>4 and concentrated. The crude was purified by column chromatography on silica gel (eluent PE:EtOAc 3:2 to 2:3) to yield the title product as a white solid (501 mg, 96%). ¹ H-NMR (400 MHz, CDCI3) 6: 7.60-7.48 (m, 4H), 7.46-7.29 (m, 7H), 7.06-6.84 (m, 2H), 4.41-4.02 (m, 2H), 3.99-3.63 (m, 2H), 3.24- 3.09 (m, 3H). UPLC-ESI (m/z): 366, 368 [M+H] ⁺ .

In a similar manner, the following compounds were prepared with the appropriate starting materials.

Derivatization of benzylamines as exemplified on compound 203

Compound 203

To the suspension of 186 (prepared according to general Route 1, 400 mg, 1.15 mmol) in DCM (15 mL), acetic anhydride (542 j L, 5.75 mmol) and triethylamine (320 p.1, 2.30 mmol) were added. The reaction mixture was stirred at room temperature for 10 min and then concentrated in vacuo. The residue was recrystallized from water/ethanol (7/1) to afford the title compound as white solid (370 mg, 83%). ¹ H NMR (300 MHz, DMSO) 6 8.94 (s, 2H), 8.70 (t, J = 5.7 Hz, 1H), 8.40 (t, J = 5.7 Hz, 1H), 7.92 - 7.63 (m, 4H), 7.59 - 7.37 (m, 3H), 7.38 - 7.22 (m, 2H), 4.53 (t, J = 5.7 Hz, 2H), 4.30 (d, J = 5.7 Hz, 2H), 3.70 (q, J = 5.7 Hz, 2H), 1.89 (s, 3H). ESI-MS (m/z): 391.3; 219.1 [M+H] ⁺

Compound 274

In identical fashion as described above, compound274 was prepared from 4-(2- acetamidoethyl)benzoic acid. The title compound was obtained as a white solid after recrystallization from EtOH/H ₂ O (5:1). ^X H NMR (400 MHz, DMSO) 8.92 (s, 2H), 8.67 (t, J = 5.6 Hz, 1H), 7.90 (t, J = 5.6 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.74 - 7.70 (m, 2H), 7.52 - 7.47 (m, 2H), 7.44 - 7.39 (m, 1H), 7.31 - 7.25 (m, 2H), 4.51 (t, J = 5.6 Hz, 2H), 3.68 (q, J = 5.6 Hz, 2H), 3.29 - 3.23 (m, 2H), 2.74 (t, J = 7.3 Hz, 2H), 1.77 (s, 3H). LC-MS: 405.4 [M+H] ⁺ . Elemental analysis (%): Calculated: C 65.39, H 6.20, N 13.24 (with 1.0 molecule of H ₂ O). Found: C 65.34, H 6.05, N 13.24. Compound 204

186 (400 mg, 1.15 mmol) was suspended in dry DCM (20 mL), then diisopropylethylamine (795 pL, 4.59 mmol) and tert-butyl [(tert-Butoxycarbonyl)amino]{[(trifluoromethyl)- sulfonyl]imino}methylcarbamate (674 mg, 1.72 mmol) was added. The reaction mixture was stirred at RT overnight and then then concentrated in vacuo. The residue was purified by reverse phase column chromatography (eluent 30-100% MeCN/l- O) to afford Boc-protected guanidine as white solid (563 mg, 83%). ^X H NMR (400 MHz, CDCI ₃ ) 6 11.47 (s, 1H), 8.66 (s, 2H), 8.59 (t, J = 5.5 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.47 - 7.39 (m, 4H), 7.38 - 7.33 (m, 1H), 7.32 - 7.27 (m, 2H), 6.72 - 6.67 (m, 1H), 4.61 (d, J = 5.5 Hz, 2H), 4.55 (t, J = 5.5 Hz, 2H), 3.88 (q, J = 5.5 Hz, 2H), 1.44 (s, 9H), 1.41 (s, 9H). ESI-MS (m/z): 591.5 [M+H] ⁺ .

The above prepared protected guanidine (563 mg, 0.95 mmol) was dissolved in DCM (10 mL) and cone. HCI (1.50 mL, 47.7 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. Ammonia (25% in water) was added until the pH of the reaction mixture reached 10 (aprox. 7 mL). Precipitates were filtered off, washed with water (3x10 mL) and recrystallized from H2O to afford the title compound as white solid (215 mg, 58%). ¹ H NMR (400 MHz, DMSO-dg) 6 (ppm): 8.93 (s, 2H), 8.82 (t, J = 5.6 Hz, 1H), 8.31 - 8.38 (m, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H), 7.53 - 7.33 (m, 9H), 4.52 (t, J = 5.6 Hz, 2H), 4.47 (d, J = 5.7 Hz, 2H), 3.71 (q, J = 5.6 Hz, 2H). ESI-MS (m/z): 391.3 [M+H] ⁺ .

Compound 205

To a solution of 186 (300 mg, 0.86 mmol) in DCM (5 mL) and ethanol (5 mL), trimethylsilyl isocyanate (233 pl, 1.72 mmol) was added. The reaction mixture was stirred at room temperature for 72 h, before it was concentrated in vacuo. The residue was purified by column chromatography (DCM/EtOH) and recrystallization from dioxane to afford the title compound as white solid (270 mg, 80%). ¹ H NMR (300 MHz, DMSO) 6 8.94 (s, 2H), 8.72 (t, J = 5.6 Hz, 1H), 7.90 - 7.76 (m, 2H), 7.77 - 7.66 (m, 2H), 7.58 - 7.39 (m, 3H), 7.39 - 7.25 (m, 2H), 6.55 (t, J = 6.1 Hz, 1H), 5.60 (s, 2H), 4.53 (t, J = 5.6 Hz, 2H), 4.23 (d, J = 6.1 Hz, 2H), 3.70 (q, J = 5.6 Hz, 2H). ESI-MS (m/z): 392.3; 220.2 [M+H] ⁺

Compound 253

A mixture of 186, 400 mg, 1.15 mmol), /V-Boc-glycine 201 mg, 1.15 mmol), HOBt (233 mg, 1.72 mmol) and NMM (0.25 mL, 2.30 mmol) in DMF (10 mL) was stirred at room temperature for 10 min. EDC-HCI (550 mg, 2.87 mmol) was added in one portion and the resulting solution was stirred at room temperature for 18h. Water (30 mL) was added and the mixture was extracted with EtOAc (3x50 mL). The combined EtOAc extracts were treated with brine (30 mL), dried over Na2SO4 and evaporated. Purification of the residue by column chromatography (eluent DCM/MeOH) yielded the Boc-protected title compound as white solid (560 mg, 96%). ¹ H-NMR 300 MHz, DMSO-dg 6 (ppm): 8.93 (s, 2H), 8.70 (t, J = 5.4 Hz, 1H), 8.34 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.45 - 7.38 (m, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.01 (t, J = 5.8 Hz, 1H), 4.51 (t, J = 5.6 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H), 3.69 (q, J = 5.4 Hz, 2H), 3.57 (d, J = 6.0 Hz, 2H), 1.39 (s, 9H). ESI (m/z): 506, 507 [M+H] ⁺ .

To solution of the above prepared protected title compound (540 mg, 1.07 mmol) in DCM (20 mL), cone. HCI (aqueous, 1 mL, 32.0 mmol) was added. The reaction mixture was stirred at room temperature for lh. Ammonia (25% in water) was added until the pH of reaction mixture reached 10 (approximately 8 mL). The mixture was extracted with EtOAc (3x20 mL). The organic extracts were combined, dried over NajSC and evaporated. Purification of the residue by column chromatography (eluent DCM/MeOH) yielded the title compound as white solid (330 mg, 76%). ¹ H-NMR 300 MHz, DMSO-dg 6 (ppm): 8.69 (t, J = 5.6 Hz, 1H), 8.37 (t, J = 5.9 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.75 - 7.69 (m, 2H), 7.54 - 7.45 (m, 2H), 7.45 - 7.38 (m, 1H), 7.33 (d, J = 8.3 Hz, 2H), 4.51 (t, J = 5.6 Hz, 2H), 4.34 (d, J = 5.9 Hz, 2H), 3.69 (q, J = 5.6 Hz, 2H), 3.15 (s, 2H), 2.22 - 1.92 (m, 2H). ESI (m/z): 406 [M+H] ⁺ .

Compound 254

A mixture of 186 (400 mg, 1.15 mmol), N,N-dimethylglycine hydrochloride (160 mg, 1.15 mmol), HOBt (233 mg, 1.72 mmol) and NMM (0.32 mL, 2.87 mmol) in DMF (10 mL) was stirred at room temperature for 10 min. EDC-HCI (550 mg, 2.87 mmol) was added in one portion and the resulting solution was stirred at room temperature for 18h. Water (30 mL) was added and the mixture was extracted with EtOAc (3x50 mL). The combined EtOAc extracts were treated with brine (30 mL), dried over Na2SO4 and evaporated. The residue was recrystallized from EtOH to afford the title compound as white powder (300 mg, 60%). ^X H-NMR 300 MHz, DMSO-dg 6 (ppm): 8.93 (s, 2H), 8.68 (t, J = 5.6 Hz, 1H), 8.35 (t, J = 6.3 Hz, 1H), 7.85 - 7.76 (m, 2H), 7.76 - 7.67 (m, 2H), 7.55 - 7.45 (m, 2H), 7.45 - 7.37 (m, 1H), 7.36 - 7.29 (m, 2H), 4.51 (t, J = 5.6 Hz, 2H), 4.32 (d, J = 6.3 Hz, 2H), 3.68 (q, J = 5.6 Hz, 2H), 2.92 (s, 2H), 2.20 (s, 6H). ESI (m/z): 434 [M+H] ⁺ .

Compound 255

In identical fashion to 253, the title compound was prepared with N-Boc-(S)-valine and was obtained as a white solid. %). ^X H-NMR 300 MHz, DMSO-dg 6 (ppm): 8.93 (s, 2H), 8.69 (t, J = 5.6 Hz, 1H), 8.38 (t, J = 6.0 Hz, 1H), 7.86 - 7.77 (m, 2H), 7.76 - 7.68 (m, 2H), 7.54 - 7.46 (m, 2H), 7.45 - 7.38 (m, 1H), 7.33 (d, J = 8.2 Hz, 2H), 4.51 (t, J = 5.6 Hz, 2H), 4.33 (d, J = 6.0 Hz, 2H), 3.68 (q, J = 5.6 Hz, 2H), 2.98 (d, J = 5.2 Hz, 1H), 1.94 - 1.81 (m, 1H), 1.77 - 1.60 (m, 2H), 0.86 (d, J = 6.8 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). ESI (m/z): 448 [M+H] ⁺ .

Compound 256

To the suspension of 123 (prepared according to general Route 1, 350 mg, 1.00 mmol) in DCM (15 mL), acetic anhydride (473 j L, 5.00 mmol) and triethylamine (279 p.1, 2.00 mmol) were added. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo and the residue was recrystallized from water/EtOH mixture (7/1) and dried in vacuo to afford the title compound as white solid (345 mg, 88 %). ^X H-NMR (300 MHz, DMSO-d6) 6 9.26 (s, 2H), 8.77 - 8.66 (m, 2H), 8.40 (t, J = 5.6 Hz, 1H), 8.05 (dt, J = 7.8, 1.1 Hz, 1H), 7.94 (td, J = 7.8, 1.8 Hz, 1H), 7.87 - 7.78 (m, 2H), 7.42 (ddd, J = 7.8, 4.8, 1.1 Hz, 1H), 7.38 - 7.28 (m, 2H), 4.55 (t, J = 5.6 Hz, 2H), 4.30 (d, J = 6.0 Hz, 2H), 3.71 (q, J = 5.6 Hz, 2H), 1.89 (s, 3H). ESI (m/z): 433 [M+H] ⁺ .

Miscellaneous Syntheses:

The following compounds were synthesized as described below:

78, 108, 135, 136, 138, 139, 141, 142, 143, 144, 164, 169, 172, 173, 174, 175, 176, 193, 203, 209, 214, 233, 234,

Synthesis of Compound 78

Compound 78

5-(Pyridin-2-yl)pyrimidine-2-thiol (550 mg, 2.91 mmol) and t-BuOK (326 mg, 2.91 mmol) were suspended in anhydrous DMF (10 mL). The yellow solution was stirred at room temperature under argon for 40 min. To the solution was added 6-chloro-2-chloromethylbenzooxazole (587 mg, 2.91 mmol). The resulting brown solution was stirred at room temperature for 3 h. To the mixture was added H2O and a light brown precipitate was filtered and washed with H2O. The solids were recrystallized from acetone to yield the product as a light brown solid (560 mg, 54 %). ¹ H NMR (300 MHz, DMSO-dg) 6: 9.29 (s, 2H), 8.75-8.63 (m, 1H), 8.13-8.02 (m, 1H), 8.00-7.87 (m, 2H), 7.76-7.62 (m, 1H), 7.48-7.33 (m, 2H), 4.85 (s, 2H). UPLC-ESI (m/z): 355, 357 [M+H ⁺ ],

Compound 108

Palladium (II) acetate (250 mg, 1.10 mmol) was added to a solution of Xantphos (850 mg, 1.46 mmol) in 1,4-dioxane (40 mL) at room temperature. The mixture was stirred under argon for 1 h and then treated with 2-chloro-5-(pyrid-2-yl)pyrimidine (700 mg, 3.65 mmol), 4-chlorophenylurea (930 mg, 5.48 mmol), potassium tert-butoxide (610 mg, 5.48 mmol) and degassed water (100 mg, 5.48 mmol). The mixture was stirred at 100 °C for 2 h, cooled to room temperature, diluted with EtOAc (100 mL) and filtered through a celite pad. After evaporation in vacuo, the crude material was purified by flash column chromatography, (eluent: 20% MeCN in DCM) to yield the product as a yellow solid. ¹ H NMR (300 MHz, DMSO-dg): 11.58 (s, 1H), 10.49 (s, 1H), 9.34 (s, 2H), 8.74-8.67 (m, 1H), 8.10-8.02 (m, 1H), 7.99-7.90 (m, 1H), 7.72-7.63 (m, 2H), 7.46-7.37 (m, 3H). UPLC-ESI (m/z): 326, 328 [M+H] ⁺ .

Compound 135

The suspension of 4-chloro-N-(2-((5-cyanopyrimidin-2-yl)oxy)ethyl)benzamide (500 mg, 1.65 mmol), sodium azide (215 mg, 3.30 mmol) and triethylammonium chloride (455 mg, 3.30 mmol) in anhydrous toluene (7 mL) was stirred at 110 °C for 20 h. After cooling to room temperature, IM NaOH (30 mL) was added and the mixture was vigorously stirred for 10 minutes. The resulting suspension was extracted with ethyl acetate (3x25 mL). The pH of the aqueous layer was adjusted to 1 by 3M HCI and extracted with ethyl acetate (3x25 mL). The combined organic layers were dried over NajSCU and evaporated (in the end co-evaporated with toluene) to afford the title compound as white solid (360 mg, 63%). ^X H NMR (300 MHz, DMSO-d6) 6 9.16 (s, 2H), 8.85 (t, J = 5.5 Hz, 1H), 7.95 - 7.80 (m, 2H), 7.63 - 7.47 (m, 2H), 4.56 (t, J = 5.6 Hz, 2H), 3.71 (q, J = 5.6 Hz, 2H). ESI (m/z): 182.1; 303.2 [M+H] ⁺ .

Compound 164

A mixture of QI (1.00 g, 2.48 mmol), trimethylsilylacetylene (686 pL, 4.96 mmol), bis(triphenylphosphine)palladium(ll) chloride (35 mg, 0.050 mmol), copper iodide (9.44 mg, 0.050 mmol) and triethylamine (690 pl, 4.96 mmol) in DMF (5 mL) was stirred at room temperature for 16 h. DCM (50 mL) was added and the organic layer was washed with water (2x30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash chromatography (hexanes/EtOAc) to afford Pl as brown solid (871 mg, 94%). ^X H NMR (400 MHz, CDCI ₃ ) 6 8.46 (s, 2H), 7.66 - 7.51 (m, 2H), 7.35 - 7.22 (m, 2H), 6.59 (s, 1H), 4.46 (t, J = 5.5 Hz, 2H), 3.79 (q, J = 5.5 Hz, 2H), 0.15 (s, 9H). ESI (m/z): 374.2; 182.0 [M+H] ⁺ .

To solution of the above prepared Pl (550 mg, 1.47 mmol) in DCM (10 mL), tetrabutylammonium fluoride (IM in THF, 1.62 mL, 1.62 mmol) was added at 0 °C. After 10 min, the reaction mixture was diluted with DCM (30 mL), extracted with water (3x20 mL) and evaporated. The residue was purified by column chromatography (hexanes/EtOAc) to afford the title compound as slightly yellow solid (370 mg, 83%). ^X H NMR (300 MHz, CDCI3) 6 8.54 (s, 2H), 7.73 - 7.57 (m, 2H), 7.39 - 7.27 (m, 2H), 6.59 (s, 1H), 4.51 (t, J = 5.5 Hz, 2H), 3.84 (q, J = 5.5 Hz, 2H), 3.22 (s, 1H). ESI (m/z): 302.1; 182.0 [M+H] ⁺ . Compound 136

A mixture of compound 164 (300 mg, 0.99 mmol), NaNs (193 mg 2.98 mmol), Cui (18.9 mg, 0.099 mmol) and sodium ascorbate (394 mg, 1.99 mmol) in DMF (5 mL) was stirred at 100 °C for 16 h. The reaction mixture was poured into water (50 mL), precipitates were filtered and purified by column chromatography (hexanes/EtOAc) to afford the title compound as slightly yellow solid (300 mg, 87%). ¹ H NMR (300 MHz, DMSO) 6 15.3 (br s, 1H), 9.06 (s, 2H), 8.83 (t, J = 5.6 Hz, 1H), 8.4 (br s, 1H), 7.98 - 7.79 (m, 2H), 7.67 - 7.45 (m, 2H), 4.52 (t, J = 5.6 Hz, 2H), 3.70 (q, J = 5.6 Hz, 2H). ESI (m/z): 345.2; 182.1 [M+H] ⁺

Compound 138

A mixture of 4-chloro-N-(2-((5-iodopyrimidin-2-yl)oxy)ethyl)benzamide (1.00 g, 2.48 mmol), Cui (94 mg, 0.50 mmol), L-proline (57 mg, 0.50 mmol), K2CO3 (685 mg, 4.96 mmol) and morpholine (324 j L, 3.72 mmol) in DMSO (15 mL) was stirred at 70 °C for 40 h. Additional portions of Cui (47 mg, 0.25 mmol), L-proline (28 mg, 0.25 mmol) were added and reaction mixture was stirred at 70 °C for an additional 30 h. EtOAc (50 mL) was added and mixture was extracted with water (3x50 mL) and brine (50 mL). The EtOAc solution was dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography (eluent DCM/acetone) and additionally by washing with EtOH/H2O (10/1, 10 mL) to afford the title compound as white powder (325 mg, 36%). ¹ H-NMR 300 MHz, CDCk 6 (ppm): 8.18 (s, 2H), 7.75 - 7.68 (m, 2H), 7.43 - 7.35 (m, 2H), 6.77 (s, 1H), 4.50 (dd, J = 5.8, 4.1 Hz, 2H), 3.92 - 3.83 (m, 6H), 3.13 - 3.06 (m, 4H). ESI (m/z): 182.1; 363.3 [M+H] ⁺ . HPLC purity 98.8%. In an identical fashion, compound 172, using piperidine instead of morpholine, was prepared: ¹ H-NMR 300 MHz, CDCk 6 (ppm): 8.78 (t, J = 5.3 Hz, 1H), 8.30 (s, 2H), 7.91 - 7.85 (m, 2H), 7.58 - 7.52 (m, 2H), 4.37 (t, J = 5.7 Hz, 2H), 3.64 (m, 2H), 3.07 (m, 4H), 1.69 - 1.58 (m, 4H), 1.56 - 1.48 (m, 2H). ESI (m/z): 182.1; 361.2 [M+H] ⁺ . HPLC purity 96.8%.

In an identical fashion, compound 173, using N-methylpiperazine instead of morpholine, was prepared: ^X H-NMR 300 MHz, CDCI ₃ 6 (ppm): 8.78 (t, J = 5.4 Hz, 1H), 8.32 (s, 2H), 7.91 - 7.85 (m, 2H), 7.58 - 7.51 (m, 2H), 4.37 (t, J = 5.7 Hz, 2H), 3.64 (m, 2H), 3.10 (m, 4H), 2.48 - 2.43 (m, 4H), 2.22 (s, 3H). ESI (m/z): 182.1; 376.3 [M+H] ⁺ . HPLC purity 99.7%.

In an identical fashion, compound 193, using 4,4-difluoropiperidine instead of morpholine, was prepared: ^X H-NMR (400 MHz, DMSO-dg) 6 (ppm): 8.78 (m, 1H), 8.39 (s, 2H), 7.90-7.85 (m, 2H), 7.57- 7.52 (m, 2H), 4.38 (m, 2H), 3.63 (m, 2H), 3.31-3.24 (m, 4H), 2.13-2.02 (m, 4H). ESI (m/z): 397.2 [M+H] ⁺ . HPLC purity 97.7%.

Compound 139

A mixture of 4-chloro-N-(2-((5-iodopyrimidin-2-yl)oxy)ethyl)benzamide (600 mg, 1.49 mmol), Pd(dba)2 (43 mg, 0.074 mmol) and X-Phos (57 mg, 0.119 mmol) in THF (15 mL) was stirred at RT for 5 min, before cyclohexylzinc bromide (3.9 mL, 1.93 mmol) was added. After 18 h, additional Pd(dba (43 mg, 0.074 mmol) and X-Phos (57 mg, 0.119 mmol) and cyclohexylzinc bromide (3.0 mL 1.5 mmol) was added and the reaction mixture was stirred for an additional 24 h. Sat. solution NH4CI (10 mL) and water (10 mL) was added. The aqueous phase was separated and extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried over NazS04 and evaporated. Purification of the residue by column chromatography (eluent DCM/acetone 5/1) yielded the title compound as yellow powder (250 mg, 46%). ^X H-NMR 300 MHz, CDCI3 6 (ppm): 8.36 (s, 2H), 7.76-7.67 (m, 2H), 7.42-7.36 (m, 2H), 6.92-6.65 (m, 1H), 4.57-4.49 (m, 2H), 3.93-3.83 (m, 2H), 2.56-2.37 (m, 1H), 1.91-1.72 (m, 5H), 1.48-1.23 (m, 5H). ESI (m/z): 360.3 [M+H] ⁺ . HPLC purity 99.4%.

In an identical fashion, compound 174, using cyclopropylzinc bromide instead of cyclohexylzinc bromide, was prepared: ¹ H NMR (300 MHz, Chloroform-d) 6 8.26 (s, 2H), 7.75 - 7.67 (m, 2H), 7.42 - 7.35 (m, 2H), 6.85 - 6.75 (m, 1H), 4.55 - 4.49 (m, 2H), 3.91 - 3.84 (m, 2H), 1.87 - 1.75 (m, 1H), 1.06 - 0.96 (m, 2H), 0.72 - 0.62 (m, 2H). ESI (m/z): 318 [M+H] ⁺ .

In an identical fashion, compound 175, using 2-norbonylzinc bromide instead of cyclohexylzinc bromide, was prepared: ^X H NMR (300 MHz, CDCI3) 6 8.37 - 8.83 (m, 2H), 7.75 - 7.68 (m, 2H), 7.41 - 7.35 (m, 2H), 6.82 (s, 1H), 4.54 (q, J = 4.9 Hz, 2H), 3.93 - 3.85 (m, 2H), 3.16 - 3.08 (m, 0.7H), 2.71 - 2.63 (m, 0.3H), 2.45 - 2.27 (m, 2H), 2.09 - 2.00 (m, 0.7H), 1.85 - 1.75 (m, 0.3H), 1.70 - 1.10 (m, 7H). ESI (m/z): 373.27 [M+H] ⁺ .

4-Chloro-/V-(2-((5-iodopyridin-2-yl)oxy)ethyl)benzamide (Rl)

To solution of 4-chloro-/V-(2-hydroxyethyl)benzamide (1.67 g, 8.35 mmol) in anhydrous THF (60 mL), NaH (60% in mineral oil, 0.25 g, 6.26 mmol) was added at 0 °C. The resulting suspension was stirred at 0 °C for 15 min. 2-Chloro-5-iodopyridine (1.00 g, 4.18 mmol) was added and the reaction mixture was stirred at room temperature for 5 days. The suspension was poured into water (250 mL). Precipitates were filtered, washed with water (2x80 mL) and dried in vacuum to afford Rl as white solid (1.5 g 89%). ^X H NMR (300 MHz, CDCI3) 6 (ppm): 8.36 - 8.26 (m, 1H), 7.82 (dd, J = 8.7, 2.4 Hz, 1H), 7.75 - 7.65 (m, 2H), 7.45 - 7.36 (m, 2H), 6.92 - 6.79 (m, 1H), 6.63 (dd, J = 8.7, 0.6 Hz, 1H), 4.54 - 4.46 (m, 2H), 3.84 (q, J = 5.3 Hz, 2H). ESI (m/z): 403, 405 [M+H] ⁺ .

Compound 141

A mixture of R1 (0.50 g, 1.24 mmol), phenylboronic acid (0.15 g, 1.24 mmol), Pd PPhah (72 mg, 0.062 mmol) and NajCOs (0.26 g, 2.48 mmol) in DMF/H2O (10/1 mL) was stirred at 100 °C for 18 h. After cooling to room temperature, DCM (50 mL) was added and the mixture washed with water (2x50 mL), dried over NajSCU, filtered and evaporated. Purification of the residue by column chromatography (eluent PE/EtOAc) yielded the title compound as white solid (350 mg, 80%). ¹ H NMR (300 MHz, CDCI3) 6 8.41 - 8.31 (m, 1H), 7.84 (dd, J = 8.6, 2.5 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.54 - 7.34 (m, 7H), 7.26 - 7.20 (m, 1H), 6.87 (dd, J = 8.6, 0.6 Hz, 1H), 4.64 - 4.57 (m, 2H), 3.88 (q, J = 5.1 Hz, 2H). ESI (m/z): 355, 353 [M+H] ⁺ .

Compound 142

2-bromopyridine (0.18 mL, 1.86 mmol) was added dropwise to a solution of n-BuLi (2M in hexane, 0.74 mL, 1.86 mmol) in THF (5 mL) at -78 °C. A solution of ZnCL (2M in MeTHF, 0.93 mL, 1.86 mmol) was added and the reaction mixture was allowed to reach room temperature. After stirring for 2 h, Pd(PPha)4 (72 mg, 0.062 mmol) and R1 (0.50 g, 1.24 mmol) was added and the mixture was stirred at room temperature for 2 h. EtOAc (10 mL) was added and the reaction mixture was filtered through a celite pad, which was rinsed with EtOAc (45 mL). The combined filtrate was evaporated and the residue was purified by reversed-phase column chromatography (eluent HjO/MeCN) to afford the title compound as white solid (0.27 g 62%). ^X H NMR (400 MHz, CDCI3) 6 (ppm): 8.73 (dd, J = 2.5, 0.7 Hz, 1H), 8.69 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.28 (dd, J = 8.7, 2.5 Hz, 1H), 7.80 - 7.71 (m, 3H), 7.66 (dt, J = 8.0, 1.0 Hz, 1H), 7.45 - 7.36 (m, 2H), 7.28 - 7.23 (m, 1H), 7.23 - 7.16 (m, 1H), 6.89 (dd, J = 8.7, 0.7 Hz, 1H), 4.65 - 4.58 (m, 2H), 3.88 (q, J = 5.2 Hz, 2H). ESI (m/z): 356, 354 [M+H] ⁺ . tert-butyl (2-((6-bromopyridin-3-yl)oxy)ethyl)carbamate (SI)

A mixture of 6-bromopyridin-3-ol (500 mg, 2.87 mmol), tert-bytyl /V-(2-bromoethyl)carbamate (2, 966 mg, 4.31 mmol) and CS2CO3 (1.40 g, 4.31 mmol) in DMF (5 mL) was stirred at 40 °C for 18h. After cooling to room temperature, water (20 mL) was added. Filtration and washing of the precipitates with water (2x10 mL) afforded SI as white powder (631 mg, 69%). ¹ H-NMR 300 MHz, CDCI3 6 (ppm): 8.06 (d, J = 3.2 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.10 (dd, J = 8.7, 3.2 Hz, 1H), 4.04 (t, J = 5.2 Hz, 2H), 3.54 (q, J = 5.2 Hz, 2H), 1.45 (s, 9H). ESI (m/z): 318 [M+H] ⁺ .

2-((6-Bromopyridin-3-yl)oxy)ethan-l-amine (S2)

To a solution of SI (795 mg, 2.51 mmol) in DCM (10 ml), TFA (3.85 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then concentrated. The residue was suspended in DCM (20 mL), extracted with NaHCOs (5% aq. 2x25 mL) and dried over Na2SO4. Concentration afforded S2 as yellowish oil which was used without further purification (540 mg, 99%). ¹ H-NMR 300 MHz, CDCk 6 (ppm): 8.07 (d, J = 3.1 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.11 (dd, J = 8.7, 3.1 Hz, 1H), 4.01 (t, J = 5.2 Hz, 2H), 3.28 - 2.97 (s, 2H). ESI (m/z): 218 [M+H] ⁺ .

/V-(2-((6-bromopyridin-3-yl)oxy)ethyl)-4-chlorobenzamide (S3)

To suspension of S2 (540 mg, 2.49 mmol) in DCM (40 mL), EtsN (0.347 mL, 2.49 mmol) was added, followed by addition of 4-chlorobenzoyl chloride (0.351 mL, 2.74 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h and concentrated. Purification of the residue by column chromatography (eluent DCM/MeOH) yielded S3 as white solid (810 mg, 92%). ¹ H-NMR 300 MHz, CDCI3 6 (ppm): 8.12 - 8.06 (m, 1H), 7.77 - 7.69 (m, 2H), 7.44 - 7.34 (m, 3H), 7.12 (dd, J = 8.7, 3.0 Hz, 1H), 6.60 - 6.51 (m, 1H), 4.18 (t, J = 5.2 Hz, 2H), 3.88 (q, J = 5.2 Hz, 2H). ESI (m/z): 357 [M+H] ⁺ .

Compound 143

A mixture of S3 (200 mg, 0.562 mmol), phenylboronic acid (103 mg, 0.844 mmol), Pd(0Ac)2 (2.53 mg, 0.011 mmol) and K3PO4 (239 mg, 1.12 mmol) in ethylene glycol (3 mL) was stirred at 80 °C for 3h. After cooling to room temperature, brine (20 mL) and EtOAc (25 mL) were added. The organic layer was separated, dried over NajSC and evaporated. Purification of the residue by flash column chromatography (eluent DCM/MeOH) yielded the title compound as white powder (135 mg, 68%). ¹ H- NMR 300 MHz, DMSO-dg 6 (ppm): 8.82 (t, J = 5.7 Hz, 1H), 8.40 (d, J = 2.9 Hz, 1H), 8.04 - 7.97 (m, 2H), 7.93 - 7.85 (m, 3H), 7.57 - 7.49 (m, 3H), 7.48 - 7.41 (m, 2H), 7.40 - 7.31 (m, 1H), 4.26 (t, J = 5.7 Hz, 2H), 3.67 (q, J = 5.7 Hz, 2H). ESI (m/z): 354 [M+H] ⁺ . Compound 144

To a solution of t-BuLi (1.7M in pentane, 0.782 mL, 1.33 mmol) in THF (8 mL) at -78 °C, 2-bromopyridine (0.796 ml, 0.831 mmol) was added. After 30 min, a solution of ZnCL (2M in MeTHF, 0.997 mL, 1.99 mmol) was added. The resulting solution was stirred at -78 °C under argon for 10 min, and then allowed to warm to room temperature. After stirring for 2 h, Pd(PPh ₃ )4 (25.6 mg, 0.0222 mmol) was added, followed by addition of S3 (195 mg, 0.548 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature under argon for 18 h and then filtered through a celite pad. The celite pad was washed with EtOAc (20 mL) the combined filtrates were evaporated and the residue was purified by flash column chromatography (DCM/MeOH). The product-containing fractions were combined and concentrated and the residue was suspended in DCM, extracted with 2M HCI (15 mL) and NaHCO ₃ solution (5% aqueous, 15 mL). Concentration of the organic layer afforded the title compound as white solid (65 mg, 33%). ^X H-NMR 300 MHz, CD ₃ OD 6 (ppm): 8.59 (d, J = 4.3 Hz, 1H), 8.37 (d, J = 2.6 Hz, 1H), 8.27 - 8.17 (m, 2H), 7.93 - 7.86 (m, 1H), 7.85 - 7.78 (m, 2H), 7.55 (dd, J = 8.8, 2.6 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.41 - 7.34 (m, 1H), 4.32 (t, J = 5.5 Hz, 2H), 3.82 (t, J = 5.5 Hz, 2H). ESI (m/z): 355 [M+H] ⁺ .

A mixture of 2-chloro-5-iodopyrimidine (750 mg, 3.12 mmol), 2-(tributylstannyl) pyrimidine (1.18 mL, 3.74 mmol, 1.2 eq), Pd(PPh ₃ )4 (150 mg, 0.13 mmol, 0.04 eq) and Cui (196 mg, 1.03 mmol, 0.33 eq) in dry DMF (10 mL) was stirred at room temperature for 80 min. The solvent was evaporated and the brown residue was purified by column chromatography (eluent petrol ether/EtOAc) to afford 2'-chloro-2,5'-bipyrimidine as orange solid (581 mg, 92%). ¹ H NMR (300 MHz, Chloroform-d) 6 9.59 (s, 2H), 8.86 (d, J = 4.9 Hz, 2H), 7.33 (t, J = 4.9 Hz, 1H). ESI (m/z): 193.0 [M+H] ⁺ .

To solution of 4-chloro-N-(2-hydroxyethyl)benzamide (363 mg, 1.82 mmol) in dry THF (15 mL), NaH (60% in mineral oil, 80 mg, 2.0 mmol, 1.1 eq) was added at 0 °C. After stirring at room temperature for 10 min, 2'-chloro-2,5'-bipyrimidine (350 mg, 1.82 mmol) was added. The reaction mixture was stirred at room temperature for 4h 30min before the solvent was evaporated and the residue was purified by column chromatography (eluent DCM/EtOH) to afford the title compound as white solid (515 mg, 80%). ^X H NMR (300 MHz, DMSO-dg) 6 9.40 (s, 2H), 8.93 (d, J = 4.9 Hz, 2H), 8.83 (t, J = 5.5 Hz, 1H), 7.90 - 7.85 (m, 2H), 7.56 - 7.49 (m, 3H), 4.56 (t, J = 5.5 Hz, 2H), 3.70 (q, J = 5.5 Hz, 2H). ESI (m/z): 356.1 [M+H] ⁺ . tert-Butyl (2-((5-bromopyrimidin-2-yl)oxy)ethyl)carbamate (Tl)

To a solution of N-Boc-ethanolamine (485 mg, 3 mmol, 1 eq) in dry THF (30 mL) at 0 °C, NaH (60% in mineral oil, 132 mg, 3.30 mmol, 1.1 eq) was added at once and the mixture was stirred for 10 min. 2- chloro-5-bromopyrimidine (580 mg, 3.0 mmol, 1 eq) was added and mixture was stirred at room temperature for lh. Water (100 mL) was added. Precipitates were filtered, washed with water (40 mL) and dried in vacuum to afford T1 as white solid (868 mg, 91%). ¹ H NMR (300 MHz, DMSO-dg) 6 8.75 (s, 2H), 7.01 (t, J = 5.7 Hz, 1H), 4.27 (t, J = 5.7 Hz, 2H), 3.30 (q, J = 5.7 Hz, 3H), 1.37 (s, 9H). LC-MS (m/z): 316 [M+H] ⁺ . tert-Butyl (2-((5-morpholinopyrimidin-2-yl)oxy)ethyl)carbamate (T2)

A mixture of T1 (860 mg, 2.70 mmol), CS2CO3 (1.20 g, 3.70 mmol, 1.55 eq), XPhos (114 mg, 0.24 mmol, 0.1 eq), Pd2(dba)s (109 mg, 0.12 mmol, 0.05 eq) and morpholine (0.47 mL, 5.40 mmol, 2 eq) in dry toluene (10 mL) was stirred at 80 °C for 23 h. After cooling to room temperature, EtOAc (50 mL) and sat. NaCI (40 mL) was added. The aqueous phase was separated and extracted with EtOAc (3x25 mL). The organic extracts were combined, dried with Na ₂ SO4 and evaporated. The residue was purified by column chromatography (hexanes/EtOAc) to afford T2 as yellow oil (745 mg, 75%). ¹ H NMR (300 MHz, Chloroform-d) 6 8.17 (s, 2H), 5.07 (s, 1H), 4.36 (t, J = 5.4 Hz, 2H), 3.91 - 3.81 (m, 4H), 3.53 (q, J = 5.4 Hz, 2H), 3.14 - 3.02 (m, 4H), 1.43 (s, 9H). ESI (m/z): 325.5 [M+H] ⁺ .

2-((5-morpholinopyrimidin-2-yl)oxy)ethan-l-ammonium chloride (T3)

To a solution of T2 (640 mg, 1.73 mmol) in dichloromethane (10 mL), 4M HCI in dioxane (1.50 mL, 6.07 mmol, 3.5 eq) was added and the solution was stirred for 18 h at room temperature before it was concentrated in vacuo. The solid residue was suspended in Et20 (50 mL) and filtered to afford T3 as light yellow solid (521 mg, 94%). 1H NMR (300 MHz, DMSO-d6) 6 8.38 (s, 2H), 8.31 (s, 2H), 4.46 - 4.40 (m, 2H), 3.80 - 3.69 (m, 4H), 3.19 (q, J = 5.6 Hz, 2H), 3.15 - 3.06 (m, 4H). ESI (m/z): 225.3 [M+H]+. Compound 209

To suspension of T3 (520 mg, 2.0 mmol), 6-chlorosalicylic acid (345 mg, 2.0 mmol) and HATU (836 mg, 2.2 mmol, 1.1 eq) in dry DMF (8 mL), DIPEA (1.0 mL, 6.0 mmol, 3 eq) was added dropwise. After stirring at room temperature for 1 h, water (100 mL) was added. The precipitates were filtered, washed with water (2x30 mL) and crystallized from EtOH to afford the title compound as beige solid (225 mg, 30%). ^X H-NMR (400 MHz, DMSO-d6) 6 12.76 (s, 1H), 9.03 (t, J = 5.6 Hz, 1H), 8.32 (s, 2H), 7.90 - 7.86 (m, 1H), 7.03 - 6.92 (m, 2H), 4.39 (t, J = 5.6 Hz, 2H), 3.75 - 3.72 (m, 4H), 3.67 (q, J = 5.6 Hz, 2H), 3.09 - 3.05 (m, 4H). ESI (m/z): 379.4 [M+H] ⁺ . Elemental analysis (%): Calculated: C 51.46, H 5.40, N 14.00 (with 0.07 molecule of EtOH and 1.0 mol. of water). Found: C 51.44, H 5.16, N 13.75. tert-Butyl (2S,4R)-2-((4-chlorobenzamido)methyl)-4-hydroxypyrrolidine-l -carboxylate (Ul)

To the solution of tert-butyl (2S,4R)-2-aminomethyl-4-hydroxypyrrolidine-l-carboxylate (415 mg, 1.92 mmol) in DCM (15 mL), p-chlorobenzoyl chloride (403 mg, 2.30 mmol) and EtaN (670 pl, 4.80 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then was poured into saturated aqueous NH4CI (20 mL). The mixture was extracted with EtOAc (3x15 mL). The organic extracts were combined and evaporated. The residue was purified by column chromatography (DCM/EtOAc) to afford Ul (490 mg, 72%) as a white foam. ^X H NMR (400 MHz, CDCI3) 6: 8.65 (s, 1H), 7.87 - 7.73 (m 2H), 7.43 - 7.35 (m, 2H), 4.50 - 4.42 (m, 1H), 4.36 - 4.22 (m, 1H), 3.74 - 3.63 (m, 1H), 3.60 - 3.52 (m, 1H), 3.45 (dd, J = 12.0, 4.6 Hz, 1H), 3.33 - 3.18 (m, 1H), 2.23 - 2.12 (m, 1H), 1.93 - 1.82 (m, 1H), 1.48 (s, 9H). LC-MS (m/z): 355.9 [M+H] ⁺ . tert-Butyl (2S,4R)-2-((4-chlorobenzamido)methyl)-4-((5-phenylpyrimidin- 2-yl)oxy) pyrrolidine-1- carboxylate (U2)

To the solution of Ul (480 mg, 1.35 mmol) in DMF (15 mL) at 0°C, NaH (60% in mineral oil, 60 mg, 1.49 mmol, 1.1 eq) was added. The reaction mixture was stirred at 0°C for 15 min. 2-Chloro-5- phenylpyrimidine (260 mg, 1.35 mmol) was added and the reaction mixture was stirred at room temperature. After 20h, the mixture was poured onto ice. Precipitates were filtered, washed with water (50 mL) and dried to afford U2 (580 mg, 84%) as white solid. ¹ H NMR (400 MHz, CDCI3) 6: 8.72 (s, 2H), 8.64 (s, 1H), 7.87 - 7.78 (m, 2H), 7.56 - 7.35 (m, 7H), 5.58 - 5.52 (m, 1H), 4.84 - 3.82 (m, 1H), 4.43 - 4.34 (m, 1H), 3.89 - 3.82 (m, 1H), 3.78 - 3.65 (m, 2H), 3.44 (m, 1H), 2.58 - 2.47 (m, 1H), 2.22 - 2.09 (m, 1H), 1.46 (s, 9H). LC-MS (m/z): 509.8 [M+H] ⁺ Compound 214

To the solution of U2 (580 mg, 1.14 mmol) in DCM (15 mL), HCI (2M in EtjO, 10 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The precipitates were filtered and washed with DCM to afford the title compound as white solid (340 mg, 73%). ¹ H NMR 6 8.87 (s, 2H), 7.94 - 7.87 (m, 2H), 7.67 - 7.61 (m, 2H), 7.56 - 7.48 (m, 4H), 7.47 - 7.41 (m, 1H), 5.82 - 5.75 (m, 1H), 4.23 - 4.12 (m, 1H), 3.90 - 3.74 (m, 3H), 3.63 (d, J = 13.1 Hz, 1H), 2.58 (dd, J = 14.5, 6.3 Hz, 1H), 2.28 (ddd, J = 14.5, 11.6, 4.8 Hz, 1H). LC-MS (m/z): 409.3 [M+H] ⁺ . Elemental analysis: Calculated: C 53.50, H 5.00, N 11.29 (with 0.8 molecule of water). Found: C 53.50, H 5.11, N 11.21. [a] _D ²⁰ -3.50 (1.0, MeOH).

Compound 215

In a similar fashion compound 215 was prepared starting from (2R,4R)-2-aminomethyl-4- hydroxypyrrolidine-l-carboxylate to afford the title compound as white solid.

¹ H NMR 6 8.87 (s, 2H), 7.92 - 7.84 (m, 2H), 7.68 - 7.60 (m, 2H), 7.56 - 7.40 (m, 5H), 5.78 - 5.73 (m, 1H), 4.13 - 4.02 (m, 1H), 3.91 - 3.83 (m, 1H), 3.82 - 3.72 (m, 2H), 3.73 - 3.67 (m, 1H), 2.87 - 2.77 (m, 1H), 2.32 -2.22 (m, 1H). LC-MS (m/z): 409.3 [M+H] ⁺ . Elemental analysis: Calculated: C 52.12, H 5.13, N 11.05 (with 1.4 molecule of water). Found: C 52.10, H 4.93, N 10.92. [a]D20 -21.1 (0.5, MeOH).

Dimethyl (4-chlorobenzoyl)carbonimidodithioate (VI)

To solution of 4-chlorobenzamide (1, 1.00 g, 6.43 mmol), carbon disulfide (1.55 mL, 25.7 mmol) and iodomethane (1.28 mL, 20.6 mmol) in DMF (15 mL), NaH (60% in mineral oil, 514 mg, 12.9 mmol) was added and the mixture was stirred at room temperature for 5 h. Cold water (30 mL) was added and mixture was extracted with EtOAc (2x50 mL). The organic extracts were combined, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (eluent EtOAc/hexanes) to afford VI as white solid (700 mg, 42%). ^X H NMR (300 MHz, DMSO) 6 8.09 - 7.99 (m, 2H), 7.63 - 7.57 (m, 2H), 2.61 (s, 6H).

4-Chloro-N-(5-hydroxytetrahydropyrimidin-2(lH)-ylidene)be nzamide (V2)

To solution of l,3-diamino-2-hydroxypropane (3, 505 mg, 5.60 mmol) in anhydrous DMF (15 mL), VI (485 mg, 1.87 mmol) was added. The reaction mixture was stirred at 85 °C for 3 h and then evaporated. The residue was purified by RP column chromatography (MeCN/water) to afford V2 as white solid (336 mg, 71%). ^X H NMR (400 MHz, DMSO) 6 8.75 (s, 2H), 8.08 - 7.95 (m, 2H), 7.48 - 7.36 (m, 2H), 5.29 - 5.17 (m, 1H), 4.00 (t, J = 4.3 Hz, 1H), 3.39 - 3.33 (m, 2H), 3.19 - 3.07 (m, 2H). ESI (m/z): 254.2 [M+H] ⁺ .

Compound 233

To solution of V2 ( 336 mg, 1.32 mmol) and 2-chloro-5-phenylpirimidine (5, 253 mg, 1.32 mmol) in THF (20 mL), NaH (60% on mineral oil, 106 mg, 2.65 mmol) was added at once. The resulting yellow suspension was stirred at room temperature for 14 h, and then poured into cold water (50 mL). Precipitates were filtered and re-crystallized from ethanol/water mixture (5/1) to afford the title compound as white solid (205 mg, 38%). ^X H NMR (400 MHz, DMSO) 6 8.98 (s, 2H), 8.91 (s, 2H), 8.08 - 8.03 (m, 2H), 7.77 - 7.73 (m, 2H), 7.54 - 7.48 (m, 2H), 7.46 - 7.40 (m, 3H), 5.52 - 5.47(m, 1H), 3.69 - 3.60 (m, 4H). ESI (m/z): 408.4 [M+H] ⁺ . Elemental analysis (%): Calculated: C 62.03, H 4.72, N 16.74 (with 0.1 molecule of H2O and 0.1 molecule of hexane). Found: C 61.93, H 4.46, N 16.67.

2-(4-Chlorophenyl)-l,4,5,6-tetrahydropyrimidin-5-ol hydrogen chloride (Wl)

The solution of l,3-diaminopropan-2-ol (788 mg, 8.74 mol) and 4-chlorothiobenzamide (1.50 g, 8.74 mol) in ethylene glycol dimethyl ether (15 mL) was stirred at reflux for 18 h, and then concentrated in vacuo. The residue was purified by RP column chromatography (MeCN/water/0.1 % HCI) to afford Wl as white solid (794 mg, 37%). ^X H NMR (400 MHz, DMSO) 6 10.27 (s, 2H), 7.87 - 7.81 (m, 2H), 7.74 - 7.67 (m, 2H), 4.27 - 4.19 (m, 1H), 3.56 - 3.49 (m, 2H), 3.41 - 3.34 (m, 2H). ESI (m/z): 211.1 [M+H] ⁺ .

Compound 234

To solution of Wl ( 774 mg, 3.21 mmol) and 2-chloro-5-phenylpirimidine (612 mg, 3.21 mmol) in THF (30 mL), NaH (60% on mineral oil, 257 mg, 6.43 mmol) was added at once. The resulting suspension was stirred at room temperature for 16 h. The suspension was poured into cold water (50 mL) and extracted with EtOAc (2x30 mL). The organic extracts were combined, dried over NajSC and evaporated. The residue was purified by flash chromatography (eluent EtOH/DCM/O.1% HCI). Product containing fractions were combined and evaporated. The residue was dissolved in DMSO (1 mL) and solution was poured into cold water (10 mL). Filtration of the precipitates yielded the title compound as white solid (335 mg, 26%). ^X H NMR (400 MHz, DMSO) 6 10.42 (s, 2H), 9.00 (s, 2H), 7.89 - 7.83 (m, 2H), 7.79 - 7.73 (m, 4H), 7.55 - 7.49 (m, 2H), 7.47 - 7.41 (m, 1H), 5.77 - 5.68 (m, 1H), 3.92 - 3.79 (m, 4H). ESI (m/z): 365.4 [M+H] ⁺ . Elemental analysis (%): Calculated: C 56.56, H 4.89, N 13.19 (with 1.3 molecule of H ₂ O). Found: C 56.52, H 4.69, N 13.02. General synthesis of 3H-l,2,4-triazino[5,6- b]indole-3-thione compounds

Isatin derivatins were reacted with thiosemicarbazide according to ACS Infect. Dis. 2018, 4, 1030 and the products used without purification unless otherwise noted. /V-substituted 2-chloroacetamides were synthesized from 2-chloroacetyl chloride and the corresponding amine or aniline, using one equivalent of base such as NEts in organic solvent such as dichloromethane. After aqueous work-up, the intermediates were used without further purification.

Synthesis exemplified on compound 15

Intermediate Al

7-trifluoromethylisatin (2.00 g, 9.30 mmol) and K2CO3 (1.54 g, 11.2 mmol) were suspended in anhydrous DMF (10 mL). The brown suspension was stirred at room temperature under argon for 40 min. To the brown suspension was added Mel (0.87 mL, 13.9 mmol). The resulting brown suspension was stirred at room temperature under argon for 16 h. To the brown suspension was added H2O (10 mL) and aq. 10% HCI. The orange precipitate was filtered off, washed with H2O and dried under vacuum to afford Al (1.77 g, 83%). ^X H-NMR (300 MHz, DMSO-dg) 6: 8.00-7.93 (m, 1H), 7.86-7.80 (m, 1H), 7.34- 7.25 (m, 1H), 3.27 (q, 7=2.5 Hz, 3H). UPLC-ESI (m/z): 230 [M+H] ⁺ .

Intermediate Bl

Intermediate Al (1.76 g, 7.68 mmol), thiosemicarbazide (700 mg, 7.68 mmol) and K2CO3 (2.65 g, 19.2 mmol) were suspended in H2O (60 mL). The yellow suspension was stirred at 120 °C. for 16 h. The resulting mixture was acidified with aqueous 10% HCI. The yellow precipitate was filtered off and dried under vacuum to afford Bl (1.96 g, 89%). ^X H-NMR (300 MHz, DMSO-dg) 6: 14.86 (s, 1H), 8.41-8.32 (m, 1H), 8.09-8.01 (m, 1H), 7.61-7.52 (m, 1H), 3.78-3.73 (m, 3H). UPLC-ESI (m/z): 285 [M+H] ⁺ .

Intermediate Cl To a solution of 4-chloroaniline HCI salt (10.0 g, 61.0 mmol) in anhydrous CH2CI2 (100 mL) was added NEta (10.2 mL, 73.2 mmol). The solution was cooled to 0 °C and chloroacetylchloride (5.80 mL, 73.2 mmol) was added dropwise. The light brown suspension was stirred at room temperature under argon for 16 h. The reaction mixture was washed with H2O (2x30 mL) and 0.5 N HCI solution (1x25 mL). The organic layer was dried over NaaSO4 and concentrated to yield Cl as a light grey solid (12.0 g, 97%). ¹ H- NMR (300 MHz, CDCIa) 6: 8.21 (br s, 1H), 7.54-7.47 (m, 2H), 7.36-7.29 (m, 2H), 4.19 (s, 2H). UPLC-ESI (m/z): 204, 206, 208 [M+H] ⁺ .

Compound 15

Bl (1.00 g, 3.52 mmol) and Cl (754 mg, 3.69 mmol) were suspended in MeOH (25 mL). To the suspension was added NEta (0.98 mL, 7.04 mmol). The resulting orange mixture was stirred at 60 °C for 18 h. The yellow precipitate was filtered off and washed with MeOH. The crude product was recrystallized from EtOAc to yield compound 15 as a white solid (1.04 g, 65 %). ¹ H-NMR (300 MHz, DMSO-dg) 6: 10.58 (s, 1H), 8.73-8.66 (m, 1H), 8.17-8.10 (m, 1H), 7.70-7.60 (m, 3H), 7.41-7.33 (m, 2H), 4.31 (s, 2H), 3.91-3.86 (m, 3H). UPLC-ESI (m/z): 452, 454 [M+H] ⁺ . In a similar manner, the following compounds were prepared with the appropriate starting materials.

Oxidations of compound 1

Compound 1 (100 mg, 0.261 mmol) was suspended in anhydrous CH2CI2 (5 mL). To the suspension was added m-CPBA (90 mg, 0.365 mmol). The initially white suspension was stirred at room temperature for 30 min. The resulting yellow suspension was washed with aq. sat. NaHCO ₃ (3x3 mL). The organic layer was dried over Na2SO4 and evaporated. The crude was suspended in EtOAc (2 mL) and filtered to yield 1-SO as a yellow solid (73 mg, 70%). ^X H NMR (CDCI3, 300 MHz) 6: 9.57 (s, 1H), 8.43-8.38 (m, 1H), 7.85-7.78 (m, 1H), 7.56-7.45 (m, 4H), 7.23-7.16 (m, 2H), 4.31 (q, 7=14.62 Hz, 2H), 3.80 (s, 3H). UPLC-ESI (m/z): 400, 402 [M+H] ⁺ .

Compound 1 (1.80 g, 4.70 mmol) was suspended in dioxane (30 mL) and magnesium monoperoxyphthalate hexahydrate (4.40 g, 14.1 mmol) was added. The yellow suspension was stirred at room temperature for 20h. The resulting yellow solution was evaporated. The crude was purified by reversed flash column chromatography on C-18-SH modified silica gel (30-70 % CH3CN in H2O) to yield the product 1-SO2 as a yellow solid (500 mg, 26%). ^X H NMR (300 MHz, DMSO-d6) 6: 10.67 (s, 1H), 8.59-8.52 (m, 1H), 8.01-7.93 (m, 2H), 7.67-7.60 (m, 1H), 7.55-7.48 (m, 2H), 7.39-7.31 (m, 2H), 4.95 (s, 2H), 3.94 (s, 3H). UPLC-ESI (m/z): 416, 418 [M+H] ⁺ .

General Synthesis of 3-ether- and 3-aminoalkyl-5H-[l,2,4]triazino[5,6-b]indol compounds

Route R1 Route R3

Route Rl: Synthesis exemplified on compound 14

Intermediate E2

4-Chloroaniline hydrochloride (1.50 g, 9.14 mmol) was dissolved in anhydrous THF (35 mL). The solution was cooled to -78°C and 2.5M n-BuLi solution in hexanes (9.2 mL, 22.9 mmol) was added dropwise. The resulting light brown solution was stirred at -78°C under argon for 30 min. To the mixture was added y-butyrolactone (1.12 mL, 13.7 mmol). The resulting solution was stirred at room temperature for 1.5 h. The reaction was quenched by addition of aq. sat. NH4CI solution (20 mL). The resulting mixture was extracted with EtOAc (3xl5mL), the organic layer was dried over NajSCU and evaporated. The crude was recrystallized from EtjO to yield DI as a white solid (1.57 g, 80%). ¹ H NMR (CDCk, 300 MHz) 6: 7.64 (s, 1H), 7.49-7.42 (m, 2H), 7.30-7.24 (m, 2H), 3.77 (t, 7=5.7 Hz, 2H), 2.53 (t, 7=6.9 Hz, 2H), 2.23-2.10 (m,), 2.03-1.92 (m, 2H). UPLC-ESI (m/z): 214, 216 [M+H] ⁺ .

Intermediate D2

Compound B2 (10.0 g, 46.2 mmol) and K2CO3 (7.67 g, 55.5 mmol) were suspended in THF (50 mL). The yellow suspension was stirred at room temperature for 40 min. To the suspension was added Mel (7.2 mL, 116 mmol). The resulting green suspension was stirred at room temperature for 4 h. To the suspension was added H2O (35 mL). The resulting mixture was extracted with CH2CI2 (4x40 mL) and the organic layer was washed with sat. NaCI (35 mL), dried over Na2SO4 and concentrated to yield D2 as a brown solid (9.91 g, 93%) which was used without further purification in the next step.

To the suspension of above methylthioether in MeOH (70 mL) and H2O (70 mL) was added oxone (52.9 g, 86.1 mmol) slowly. The resulting yellow suspension was stirred at room temperature for 16 h. The before it was filtered. The yellow solid was dissolved in MeCN and the insoluble part (impurities) was filtered off. The filtrate was evaporated to yield D2 as a yellow solid (8.03 g, 71 %). ¹ H-NMR (300 MHz, DMSO-dg) 6: 8.56-8.50 (m, 1H), 7.99-7.90 (m, 2H), 7.65-7.57 (m, 1H), 3.95 (s, 3H), 3.58 (s, 3H). UPLC- ESI (m/z): 263 [M+H] ⁺ .

Compound 14

60% NaH dispersion on mineral oil (0.26 g, 6.48 mmol) was suspended in anhydrous DMF (5 mL). The suspension was cooled to 0 °C and compound E2 (1.38 g, 6.48 mmol) was added. The resulting light brown suspension was stirred at 0 °C under argon for 40 min. To the suspension was added compound D2 (1.00 g, 3.81 mmol) and the resulting mixture was stirred at room temperature under argon for 16 h. The orange mixture was evaporated in vacuo and the residue was washed with H2O (5 mL) and hot MeCN (3x10 mL). The light yellow precipitate was filtered off and dried under vacuum to obtain 14 (1.18 g, 78 %). ^X H NMR (CDCI3, 300 MHz) 6: 10.10 (s, 1H), 8.31-8.25 (m, 1H), 7.76-7.67 (m, 2H), 7.65- 7.56 (m, 2H), 7.50-7.40 (m, 1H), 7.36-7.28 (m, 2H), 4.59 (t, 7=6.3 Hz, 2H), 3.75 (s, 3H), 2.56 (t, 7=7.5 Hz, 2H), 2.21-2.09 (m, 2H). UPLC-ESI (m/z): 396, 398 [M+H] ⁺ .

Route R2: Synthesis exemplified on compound 40-(R)

Intermediate F2

Compound D2 (6.70 g, 25.5 mmol) and NaOH (5.11 g, 128 mmol) were suspended in H2O (120 mL). The yellow suspension was stirred at room temperature for 3 h. The resulting brown solution was acidified with aq. 10% HCI solution to pH = 1. The yellow precipitate was filtered off and dried under vacuum (4.97 g, 97%) and used without further purification in the next step.

The above prepared crude intermediate (7.30 g, 36.5 mmol) was suspended in POCI3 (20 mL). The yellow suspension was stirred at 85 °C for 2 h. The resulting brown suspension was poured into ice/HjO. The aq. layer was extracted with CHCU/'PrOH 3:1 (3x70 mL). The organic layer was dried over NajSC and concentrated. The brown sticky residue was crystallized from MeOH, the brown precipitate was filtered and dried under vacuum to afford F2 (5.84 g, 73%). ¹ H-NMR (300 MHz, DMSO- d ₆ ) 6: 8.45-8.39 (m, 1H), 7.90-7.82 (m, 2H), 7.60-7.51 (m, 1H), 3.85 (s, 3H). UPLC-ESI (m/z): 219, 221 [M+H] ⁺ . Intermediate G1

Boc-L-Pro (1.00 g, 4.65 mmol), 4-chloroaniline hydrochloride (838 mg, 5.11 mmol), EDC*HCI (2.22 g, 11.6 mmol) and HOBt (1.07 g, 6.98 mmol) were suspended in anhydrous CH2CI2 (30 mL). The suspension was cooled to 0°C, and EtaN (2.33 mL, 16.7 mmol) was added. The resulting light brown solution was stirred at room temperature under argon for 3h. To the mixture was added H2O (15 mL), the resulting mixture was extracted with CH2CI2 (3x20 mL), the organic layer was dried over Na2SO4 and evaporated. The crude product was purified by reversed phase column flash chromatography on C-18-SH modified silica gel (10 - 85 % MeCN in H2O) to yield G1 as a white solid (931 mg, 62%). ¹ H NMR (CDCk, 300 MHz) 6: 9.62 (s, 1H), 7.49-7.42 (m, 2H), 7.29-7.19 (m, 2H), 4.53-4.34 (m, 1H), 3.52-3.28 (m, 2H), 2.61-2.40 (m, 1H), 2.06-1.84 (m, 3H), 1.49 (s, 9H). UPLC-ESI (m/z): 323, 325 [M-H]’.

Intermediate Hl

The above prepared G2 (931 mg, 2.87 mmol) was dissolved in anhydrous CH2CI2 (6 mL). The solution was cooled to 0°C, and TFA (4 mL) was added dropwise. The solution was stirred at room temperature for 1 h. The resulting light brown solution was washed with sat. NaHCOs (3x3 mL), the organic layer was evaporated and dried under vacuum to yield Hl as a light brown solid (550 mg, 86%). ¹ H NMR (CDCk, 300 MHz) 6: 9.79 (s, 1H), 7.61-7.51 (m, 2H), 7.31-7.23 (m, 2H), 3.91-3.81 (m, 1H), 3.15-3.04 (m, 1H), 3.02-2.93 (m, 1H), 2.29-2.17 (m, 1H), 2.15-2.09 (m, 1H), 2.08-1.97 (m, 1H), 1.83-1.69 (m, 2H). UPLC-ESI (m/z): 225, 227 [M+H] ⁺ .

Compound 40-(R)

Intermediates F2 (452 mg, 2.07 mmol) and Hl (605 mg, 2.69 mmol) were dissolved in anhydrous 1,4- dioxane (15 mL). To the solution was added DIPEA (0.55 mL, 3.19 mmol). The dark green solution was stirred at 110°C under argon for 16h. To the resulting brown solution was added H2O (10 mL) and the mixture was extracted with EtOAc (3x10 mL). The organic layer was dried over NajSC and evaporated. The crude was purified by reversed phase column chromatography on C-18-SH modified silica gel (15 to 85 % MeOH in H2O) and recrystallized from MeCN to yield 40-(R) light yellow solid (623 mg, 74%). [a]= -3.91 (IM CHCI3). ^X H NMR (300 MHz, DMSO-dg) 6: 10.36 (s, 1H), 8.17-8.04 (m, 1H), 7.70-7.51 (m, 4H), 7.40-7.29 (m, 3H), 4.99-4.52 (m, 1H), 4.01-3.40 (m, 5H), 2.52-2.29 (m, 1H), 2.21-1.94 (m, 3H). UPLC-ESI (m/z): 407, 409 [M+H] ⁺ .

Route R3: Synthesis exemplified on compound 71

Intermediate 11 Compound D2 (6.70 g, 25.5 mmol) and NaOH (5.11 g, 128 mmol) were suspended in H2O (120 mL). The yellow suspension was stirred at room temperature for 3 h. The resulting brown solution was acidified with aq. 10% HCI solution to pH = 1. The yellow precipitate was filtered off and dried under vacuum to afford 11 (4.97 g, 97%). ^X H-NMR (300 MHz, DMSO-dg) 6: 13.01 (s, 1H), 7.94-7.88 (m, 1H), 7.65-7.57 (m, 1H), 7.55-7.49 (m, 1H), 7.35-7.27 (m, 1H), 3.55 (s, 3H). UPLC-ESI (m/z): 201 [M+H] ⁺ .

Compound 71

Compound 11 (673 mg, 3.36 mmol), 6-chloro-2-chloromethylbenzooxazole (1.02 g, 5.04 mmol) and K2CO3 (512 mg, 3.70 mmol) were suspended in anhydrous DMF (44 mL). The resulting yellow suspension was stirred at room temperature under argon for 18 h. The suspension was poured into H2O and acidified to pH = 1 with aq. 10% HCI. The yellow precipitate was filtered and recrystallized from MeOH to yield 71 as a yellow solid (929 mg, 76%). ^X H-NMR (300 MHz, DMSO-dg) 6: 7.98-7.90 (m, 2H), 7.75-7.62 (m, 2H), 7.61-7.54 (m, 1H), 7.46-7.40 (m, 1H), 7.38-7.30 (m, 1H), 5.71 (s, 2H), 3.59 (s, 3H). UPLC-ESI (m/z): 366, 368 [M+H] ⁺ .

In a similar manner, the following compounds were prepared with the appropriate starting materials.

General Synthesis of Bicyclic Aromatics and JV-methylamides:

Synthesis exemplified on compound 571

2-(Quinolin-7-yloxy)acetonitrile

7-Hydroxyquinoline (1.72 g, 11.8 mmol) was dissolved in acetone/DMF 10:1 mixture (55 mL) and K2CO3 (3.27 g, 23.69 mmol) followed by bromoacetonitrile (0.95 ml, 14.21 mmol) was added. The mixture was stirred at room temperature for 20 hours. Solvents were evaporated and to the residue was added H2O (30 mL). The mixture was extracted with EtOAc (3x40 mL), the combined organic layers were washed with brine and H2O, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (eluent: EtOAc/petrol ether 1:2 to 1:1). The title compound was isolated as a light yellow solid (1.80 g, 82%). ^X H NMR (300 MHz, CDCI3) 6: 8.88 (dd, 7=4.5 Hz, 1.8 Hz, 1H), 8.14 (dd, 7=8.4 Hz, 1.2 Hz, 1H), 7.79 (d, 7=9.3 Hz, 1H), 7.52 (d, 7=2.7 Hz, 1H), 7.36 (m, 1H), 7.25-7.29 (m, 1H), 4.92 (s, 2H). UPLC-ESI (m/z): 185 [M+H] ⁺ .

2-(Quinolin-7-yloxy)ethan-l-amine (JI)

LiAIH4 (742 mg, 19.54 mmol) was suspended in anhydrous Et20 (150 mL). The suspension was cooled to 0 °C. To the suspension was added a solution of 2-(quinolin-7-yloxy)acetonitrile (1.80 g, 9.77 mmol) in Et20 (150 ml). The reaction mixture was stirred 1 hour at 0 °C, then at room temperature for 18h. The resulting mixture was cooled to 0 °C and H2O (20 ml) was added dropwise. The mixture was extracted with EtOAc (3x30 mL). The organic layer was washed with brine, H2O, dried over Na2SO4, and evaporated. The crude was washed with Et20 and dried under vacuum to yield light brown oil which was used without further purification (1.15 g, 62%). ¹ H NMR (300 MHz, CDCI3) 6: 8.76 (dd, 7=4.2, 1.5 Hz, 1H), 8.01 (d, 7=9.0 Hz, 1H), 7.63 (d, 7=9.0 Hz, 1H), 7.34 (d, 7=2.4 Hz, 1H), 7.22-7.13 (m, 2H), 3.11 (t, 7=5.1 Hz, 2H), 2.71-7.21 (m, 2H).

Compound 57

The above prepared 2-(Quinolin-7-yloxy)ethan-l-amine (1.15 g, 6.11 mmol) and 4-chlorobenzoyl chloride (0.93 ml, 7.33 mmol) were suspended in anhydrous CH2CI2 (100 mL). To the yellow suspension was added NEt3 (1.70 mL, 12.2 mmol). The resulting yellow solution was stirred at room temperature under argon for 16 h. The orange solution was diluted with H2O (15 mL) and the resulting mixture was extracted with CH2CI2 (2x100 mL), dried over NajSCU and evaporated. The crude was purified by column chromatography on silica gel (eluent PE/EtOAc l:5->100% EtOAc gradient, then C^CL/MeOH 20:1). The combined product-containing fractions were concentrated and the residue was washed with Et20 to yield the product as light yellow solid (650 mg, 33 %), Rf=0.22 (C^CL/MeOH 1:9). ¹ H NMR (300 MHz, DMSO-dg) 6: 8.89-8.76 (m, 2H), 8.30-8.22 (m, 1H), 7.94-7.82 (m, 3H), 7.57-7.49 (m, 2H), 7.45-7.41 (m, 1H), 7.40-7.33 (m, 1H), 7.30-7.23 (m, 1H), 4.30 (t, 7=5.8 Hz, 2H), 3.77-3.67 (m, 2H). UPLC-ESI (m/z): 327, 329 [M+H] ⁺ .

Compound 571

Cmpd 57 (190 mg, 0.580 mmol) was dissolved in anhydrous THF (8 mL). The solution was cooled to 0 °C and 60% NaH in mineral oil (35 mg, 0.87 mmol) was added. The resulting suspension was stirred at 0 °C under argon for 20 min. To the suspension was added Mel (0.04 mL, 0.70 mmol). The resulting mixture was stirred at room temperature under argon for 16h. The reaction was quenched with H2O (15 mL) and extracted with CH2CI2 (3x20 mL). The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (eluent PE:EtOAc:MeOH 3:1:1 to 0:10:1) gave the product as an orange oil (193 mg, 97%). ¹ H-NMR (400 MHz, CDCI3) 6: 8.89-8.80 (m, 1H), 8.16-8.07 (m, 1H), 7.74 (d, 7=9.0 Hz, 1H), 7.55-7.28 (m, 6H), 7.27-7.13 (m, 1H), 4.52-4.11 (m, 2H), 4.08-3.68 (m, 2H), 3.16 (s, 3H). UPLC-ESI (m/z): 341, 343 [M+H] ⁺ .

In a similar manner, the following compounds were prepared with the appropriate starting materials. Miscellaneous Syntheses:

The following compounds were synthesized as described below:

4, 11, 20, 20-SO, 20-SO2, 65, 66, 67, 75, 76

Synthesis of Compound 20

2-Bromo-9-methyl-9H-carbazole (KI)

2-bromocarbazole (3.00 g, 12.2 mmol) was dissolved in DMSO (10 mL). To the solution was added NaOH (0.975 g, 24.4 mmol) as a solution in H2O (2 mL). To the resulting light brown solution was slowly added Mel (1.50 mL, 24.4 mmol). The resulting mixture was stirred at room temperature for 18h. To the mixture was added aq. sat. NaCI solution (10 mL). The resulting mixture was extracted with CH2CI2 (4xl5mL). The combined organic layers were dried over Na2SO4 and concentrated. To the resulting brown solution (product + DMSO) was added H2O (10 mL) and the light brown precipitate was filtered off. The crude was recrystallized from MeOH to yield the title product as a white solid (1.88 g, 60%). ^X H NMR (300 MHz, CDCI ₃ ) 6: 8.09-8.02 (m, 1H), 7.97-7.90 (m, 1H), 7.58-7.46 (m, 2H), 7.43-7.30 (m, 2H), 7.29-7.21 (m, 1H), 3.81 (s, 3H).

9-Methyl-9H-carbazole-2-thiol (K2)

The above prepared 2-bromo-9-methyl-9H-carbazole (1.86 g, 7.15 mmol) was dissolved in anhydrous THF (40 mL). The solution was cooled to -78 °C and 1.9 M t-BuLi solution in pentane (8.94 mL, 14.3 mmol) was added dropwise. The resulting light green suspension was stirred at -78 °C under argon for 30 min. To the suspension was added elemental sulfur (0.252 g, 7.87 mmol). The resulting yellow suspension was stirred at room temperature under argon for 18 h. To the suspension was added sat. NH4CI (20mL). The resulting mixture was extracted with EtOAc (3x20mL). The combined organic layer were dried over Na2SO4 and evaporated to yield a yellow solid (mixture of title product, disulfide K3, and unidentified byproducts). Disulfide K3 was separated by dissolving the mixture in hot MeOH (15 ml) and filtration. The solids were collected and reduced by reduction with LiAl H4. The filtrate and the crude reduced product K2 were combined, concentrated and used without further purificiation (554 mg; mixture contains title compound as general component "'0.320 g, 54% by LC-MS peak areas). Compound 20

The above prepared crude K2 (870 mg, 4.08 mmol) was dissolved in anhydrous DMF (8 mL). The light yellow solution was cooled to 0 °C and 60% NaH in mineral oil (0.196 g, 4.89 mmol) was added. The resulting mixture was stirred at 0 °C under argon for 40 min. To the resulting yellow solution was added Cl (0.916 g, 4.49 mmol). The mixture was stirred at 65 °C under argon for 16 h. To the resulting dark brown suspension was added H2O (10 mL) and the liquid decanted. The brown sticky residue was purified by column chromatography on silica gel (eluent: 0 - 7% MeOH in DCM). The light brown solid thus obtained was washed with hot MeOH (7 mL) and the crude was recrystallized from acetone to yield the product as a white solid (684 mg, 44 %). ¹ H NMR (DMSO-dg, 300 MHz) 6: 10.37 (s, 1H), 8.14- 8.06 (m, 2H), 7.67-7.55 (m, 4H), 7.48-7.42 (m, 1H), 7.38-7.32 (m, 2H), 7.26-7.26 (m, 2H), 3.96 (s, 2H), 3.83 (s, 3H). UPLC-ESI (m/z): 381, 383 [M+H] ⁺ .

Synthesis of Compound Cmpd 20-SO

Compound 20-SO

Compound 20 (1.00 g, 2.63 mmol) was suspended in chloroform (20 mL) and heated until a clear solution was obtained. To the warm solution, 75% m-chloroperoxybenzoic acid (478 mg, 1.97 mmol) was added. The resulting yellow suspension was stirred at room temperature for 20 min. The yellow solution was evaporated and the residue was purified by flash column chromatography (0-10 % EtOH in CH2CI2) to yield the product as a yellowish solid (716 mg, 92%). ¹ H NMR (300 MHz, CDCI3) 6: 9.17 (s, 1H), 8.19-8.16 (m, 1H), 8.11-8.07 (m, 1H), 7.73-7.70 (m, 1H), 7.57-7.51 (m, 1H), 7.48-7.42 (m, 2H), 7.41- 7.36 (m, 1H), 7.35-7.32 (m, 1H), 7.31-7.27 (m, 1H), 7.26-7.22 (m, 2H), 3.99 (d, J=14.4 Hz, 1H), 3.70 (s, 3H), 3.65 (d, J=14.4 Hz, 1H). UPLC-ESI (m/z): 397, 399 [M+H] ⁺ .

Synthesis of Compound 20-SO2

Cmpd 20-SO2

Compound 20 (761 mg, 2.00 mmol) was suspended in chloroform (20 mL) and heated until a clear solution was obtained. To the warm solution of 75% meto-chloroperoxybenzoic acid (1.033 g, 4.50 mmol) was added. The yellow suspension was stirred at room temperature for 20 min. The resulting yellow suspension was stirred at room temperature for 20 min. The yellow solution was evaporated and the residue was purified by flash column chromatography (0-15 % EtOH in CH2CI2). The productcontaining fractions were evaporated and the residue recrystallized from EtOH to yield the product as a brownish solid (365 mg, 44%). ^X H NMR (400 MHz, CDCI3) 6: 8.66 (s, 1H), 8.24 (d, 7=8.2 Hz, 1H), 8.15 (d, 7=7.8 Hz, 1H), 7.98-7.95 (m, 1H), 7.76-7.71 (m, 1H), 7.64-7.58 (m, 1H), 7.52-7.45 (m, 3H), 7.36-7.28

(m, 3H), 4.24 (s, 2H), 3.86 (s, 3H). UPLC-ESI (m/z): 413, 415 [M+H] ⁺ .

Synthesis of Compound 4

Ethyl (E)-3-(5-methyl-5H-[l,2,4]triazino[5,6-b]indol-3-yl)acrylate (LI)

3-Chloro-5-methyl-5H-[l,2,4]triazino[5,6-b]indole (F2, 1.72 g, 7.82 mmol), ethyl 3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (2.12 g, 9.38 mmol), Pd(dppf)Cl2 (400 mg, 0.547 mmol) and K3PO4 (4.98 g, 23.5 mmol) were suspended in anhydrous 1,4-dioxane (15 mL). The brown suspension was stirred at 120°C under argon for 16 h. The resulting brown suspension was filtered through a celite pad, which was washed with EtOAc (120 mL). The combined filtrate was evaporated. The crude was purified by column chromatography on silica gel; eluent - PE/EtOAc 10:1 to 2:1 to yield LI as yellow solid (728 mg, 33%). R _f =0.42 (PE/EtOAc 1:1). ^X H-NMR (300 MHz, DMSO-dg) 6: 8.47-8.42 (m, 1H), 7.89-7.84 (m, 2H), 7.83 (d, 7=15.7 Hz, 1H), 7.58-7.49 (m, 1H), 7.26 (d, 7=15.7 Hz, 1H), 4.27 (q, 7=7.1 Hz, 2H), 3.91 (s, 3H), 1.31 (t, 7=7.1 Hz, 3H). UPLC-ESI (m/z): 283 [M+H] ⁺ .

Ethyl 3-(5-methyl-5H-[l,2,4]triazino[5,6-b]indol-3-yl)propanoate (L2)

Compound 9 (2.65 g, 9.39 mmol) was suspended in EtOAc (120 mL). To the yellow suspension was added 10% palladium on carbon (999 mg, 0.939 mmol). The resulting black suspension was stirred at room temperature in a presence of H2 (1 atm, bubbling through mixture) for 16 h. The dark suspension was filtered through a celite pad which was washed with EtOAc (60 mL). The combined filtrate was concentrated to yield L2 as a light yellow solid which was used without further purification (2.59 g, 97%). ^X H-NMR (300 MHz, DMSO-dg) 6: 8.43-8.37 (m, 1H), 7.85-7.76 (m, 2H), 7.55-7.45 (m, 1H), 4.07 (q, 7=7.1 Hz, 2H), 3.85 (s, 3H), 3.41 (t, 7=7.1 Hz, 2H), 2.96 (t, 7=7.1 Hz, 2H), 1.16 (t, 7=7.1 Hz, 3H). UPLC-ESI (m/z): 285 [M+H] ⁺ .

3-(5-Methyl-5H-[l,2,4]triazino[5,6-b]indol-3-yl)propanoic acid (L3)

Compound L2 (2.56 g, 9.00 mmol) and LiOH*H2O (2.65 g, 63.0 mmol) were suspended in EtOH (150 mL). The yellow suspension was stirred at 90 °C for 3h before the mixture was concentrated in vacuo. The crude was dissolved in H2O, acidified with IM HCI solution in H2O to pH=l. The aqueous layer was saturated with NaCI and extracted with CHCU/'PrOH 3:1 (4x70 mL). The organic layer was dried over Na2SO4 and concentrated to yield L3 as a yellow solid which was used without further purification (1.91 g, 83%). ^X H-NMR (300 MHz, DMSO-dg) 6: 8.46-8.40 (m, 1H), 7.92-7.84 (m, 2H), 7.62-7.54 (m, 1H), 3.91 (s, 3H), 3.41 (t, 7=7.1 Hz, 2H), 2.94 (t, 7=7.1 Hz, 2H). UPLC-ESI (m/z): 257 [M+H] ⁺ . Compound 4

Compound L3 (549 mg, 2.14 mmol), 4-chloroaniline (410 mg, 3.22 mmol) and HATU (1.30 g, 3.43 mmol) were suspended in anhydrous DMF (18 mL). To the suspension was added NEt3 (0.90 mL, 6.43 mmol). The resulting dark purple solution was stirred at room temperature under argon for 16 h. Volatiles were evaporated. To the black residue was added EtOAc (35 mL) and H2O (20 mL). Insoluble black sticky precipitates (impurities) was filtered off and the filtrate layers were separated. The organic layer was washed with IM HCI (1x20 mL) and brine (1x20 mL), dried over NajSC and concentrated. The crude was purified by column chromatography on silica gel (eluent PE/EtOAc 10:1 to 1:5) to yield the title compound as a light brown solid (321 mg, 41%). Rf=0.42 (EtOAc). ¹ H-NMR (300 MHz, DMSO-dg) 6: 10.24 (s, 1H), 8.44-8.37 (m, 1H), 7.86-7.78 (m, 2H), 7.69-7.61 (m, 2H), 7.56-7.47 (m, 1H), 7.39-7.31 (m, 2H), 3.85 (s, 3H), 3.47 (t, 7=7.3 Hz, 2H), 3.02 (t, 7=7.3 Hz, 2H). UPLC-ESI (m/z): 366, 368 [M+H] ⁺ .

Synthesis of compound 11

Ethyl 5-methyl-5H-[l,2,4]triazino[5,6-b]indole-3-carboxylate (Ml)

N-Methylisatin (369 mg, 2.29 mmol) was dissolved in TFA (3 mL). To the dark red solution was added ethyl 2-hydrazineyl-2-iminoacetate (300 mg, 2.29 mmol). The dark red solution was stirred at room temperature for 30 min., then concentrated in vacuo. The dark red sticky residue was dissolved in POCI3 (2.1 mL, 22.9 mmol) and the brown solution was stirred at 140 °C under argon for 16 h. The resulting black solution was slowly poured in MeOH at 0°C and the resulting solution was evaporated. The crude was purified by column chhromatography on silica gel, eluent PE/EtOAc 10:1 to 1:10 (gradient). The resulting brown oily crude was dissolved in EtOAc (20 mL) and washed with H2O (3x10 mL). The organic layer was dried over Na2SO4 and concentrated to yield a brown solid (101 mg, 17%). R _f = 0.28 (PE/EtOAc 1:2). ^X H-NMR (300 MHz, CDCI3) 6: 8.65-8.58 (m, 1H), 7.88-7.79 (m, 1H), 7.62-7.51 (m, 2H), 4.63 (q, 7=7.2 Hz, 2H), 4.01 (s, 3H), 1.53 (t, 7=7.2 Hz, 3H). UPLC-ESI (m/z): 257 [M+H] ⁺ .

5-Methyl-5H-[l,2,4]triazino[5,6-b]indole-3-carboxylic acid (M2)

Compound Ml (95 mg, 0.371 mmol) and LiOH (53 mg, 2.22 mmol) were suspended in EtOH (3 mL). The brown suspension was stirred at room temperature for 1 h, then concentrated. The crude was suspended in H2O, and acidified with 10% HCI to pH=l. Precipitates (impurities) were filtered off and the aqueous layer was extracted with CHCU/z-PrOH 3:1 (3x20 mL). The organic layer was dried over Na2SO4 and evaporated to yield a yellow solid which was used without further purification (59 mg, 70%). ^X H-NMR (300 MHz, DMSO-dg) 6: 8.53-8.48 (m, 1H), 7.94-7.86 (m, 2H), 7.61-7.53 (m, 1H), 3.93 (s, 3H). UPLC-ESI (m/z): 229 [M+H] ⁺ . Compound 11

Compound M2 (59 mg, 0.259 mmol), 2-amino-/V-(4-chlorophenyl) acetamide trifluoroacetate salt (57 mg, 0.259 mmol), H0Bt*H20 (48 mg, 0,310 mmol) and EDC*HCI (59 mg, 0,310 mmol) were suspended in anhydrous CH2CI2 (4 mL). To the suspension was added NEta (108 pL, 0.776 mmol). The resulting yellow suspension was stirred at room temperature under argon for 16 h. The yellow precipitate was filtered and dried under vacuum to afford the title compound (31 mg, 30 %). ¹ H-NMR (300 MHz, DMSO- d ₆ ) 6: 10.26 (s, 1H), 9.45 (t, 7=5.8 Hz, 1H), 8.55-8.48 (m, 1H), 7.95-7.87 (m, 2H), 7.69-7.62 (m, 2H), 7.61- 7.54 (m, 2H), 7.42-7.34 (m, 2H), 4.22 (d, 7=5.8 Hz, 2H), 3.96 (s, 3H). UPLC-ESI (m/z): 395, 397 [M+H] ⁺ .

Synthesis of Compound 38

5-Methyl-5H-[l,2,4]triazino[5,6-b]indole-3-carbonitrile (M4)

Sulfone derivative D2 (2.00 g, 7.62 mmol) and NaCN (419 mg, 8.54 mmol) were suspended in anhydrous DMF (10 mL). The resulting suspension was stirred at room temperature under argon for 1 h. The resulting brown suspension was diluted with H2O (20 mL). The light brown precipitate was filtered and dried under vacuum (1.19 g, 75%). ^X H NMR (300 MHz, DMSO-d ₆ ) 6: 8.56-8.51 (m, 1H), 8.00- 7.92 (m, 2H), 7.68-7.57 (m, 1H), 3.93 (s, 3H). UPLC-ESI (m/z): 210 [M+H] ⁺ .

Methyl 5-methyl-5H-[l,2,4]triazino[5,6-b]indole-3-carboxylate (M5)

Nitrile derivative M4 (1.11 g, 5.31 mmol) was suspended in HCI (g.) saturated anhydrous MeOH (60 mL). The resulting yellow suspension was stirred at 60 °C under argon for 48 h. To the suspension was added H2O (40 mL), the resulting mixture was stirred at room temperature for 1 h. The yellow precipitate was filtered, washed with H2O, and dried under vacuum (806 mg, 63%). ¹ H NMR (300 MHz, DMSO-dg) 6: 8.56-8.48 (m, 1H), 8.00-7.84 (m, 2H), 7.65-7.53 (m, 1H), 4.01 (s, 3H), 3.93 (s, 3H). UPLC- ESI (m/z): 243 [M+H] ⁺ .

Compound 38 l-(4-Chlorophenyl)piperazine (M6, 750 mg, 3.81 mmol) and AICI3 (573 mg, 7.95 mmol) were suspended in anhydrous CH2CI2 (35 mL). The yellow suspension was stirred at room temperature under argon for 1 h. To the mixture was added compound M5 (770 mg, 3.18 mmol). The resulting orange suspension was stirred at room temperature under argon for 24 h. To the mixture was added 50 mL aq. IM HCI. The yellow precipitate was filtered off and recrystallized from DMSO/H2O mixture to yield the title compound as a yellow solid (134 mg, 10%). ^X H NMR (300 MHz, DMSO-dg) 6: 8.51-8.45 (m, 1H), 7.93- 7.84 (m, 2H), 7.61-7.52 (m, 1H), 7.30-7.21 (m, 2H), 7.04-6.95 (m, 2H), 3.93-3.84 (m, 5H), 3.46-3.38 (m, 2H), 3.32-3.24 (m, 2H), 3.15-3.07 (m, 2H). UPLC-ESI (m/z): 407, 409 [M+H] ⁺ .

Synthesis of Compound 65

EDCI, DMAP

Compound 65

Benzo[b]thiophene-2-carboxylic acid (900 mg, 5.05 mmol), 4-chloroaniline hydrochloride (870 mg, 5.30 mmol) and DMAP (250 mg, 2.02 mmol) were dissolved in CH2CI2 (30 mL). NMM (920 mg, 9.09 mmol) was added and reaction mixture was stirred 10 min at room temperature. 3- (Ethyliminomethyleneamino)-/V,/\/-dimethylpropan-l-amine hydrochloride (1.45 g, 7.58 mmol) was added in one portion and the resulting solution was stirred at room temperature for 16 h. The resulting suspension was evaporated in vacuo and the residue suspended in a small amount of CH2CI2. The solids were collected by filtration and washed with a minimum of CH2CI2 to give desired product as a white solid (1.23 g, 85%). 1H-NMR (300 MHz, DMSO-dg): 10.63 (s, 1H), 8.38-8.35 (m, 1H), 8.10-7.98 (m, 2H), 7.85-7.77 (m, 2H), 7.54-7.40 (m, 4H). UPLC-ESI (m/z): 288, 290 [M+H] ⁺ .

Synthesis of Compound 66

Compound 66 l-Benzothiophen-2-ylmethamine hydrochloride (930 mg, 4.66 mmol) was suspended in anhydrous CH2CI2 (12 mL) and cooled to 0 °C. To the suspension were added 4-chlorobenzoyl chloride (980 mg, 5.58 mmol) and EtaN (1.40 g, 14.0 mmol). The suspension was stirred at rom temperature under argon for 1 h. To the mixture was added H2O (10 mL). The resulting mixture was extracted with CH2CI2 (3x10ml). The combined organic layers were dried over Na2SC>4 and concentrated. The crude was recrystallized from EtOAc/PE to yield the title product as a white solid (520 mg, 37%). ¹ H-NMR (300 MHz, DMSO-dg): 9.34 (t, 7=5.8 Hz, 1H), 7.96-7.85 (m, 3H), 7.81-7.75 (m, 1H), 7.60-7.52 (m, 2H), 7.38- 7.25 (m, 3H), 4.74 (d, 7=5.8 Hz, 2H). UPLC-ESI (m/z): 302, 304 [M+H] ⁺ .

Synthesis of Compound 67

Compound 67

Benzo[b]thiophene-2-boronic acid (1.14 g, 6.38 mmol), 2,6-dichlorobenzoxazole (1.00 g, 5.32 mmol),

KOAc (1.04 g, 10.6 mmol) and Pd(Amphos)Cl2 (190 mg, 0.270 mmol) were suspended in a mixture of 1,4-dioxane (20 mL) and H2O (2 mL) and the suspension was stirred at 100 °C for 16 h. After the reaction mixture was cooled to ambient temperature, H2O was added. The precipitate was filtered and washed with H2O and EtOAc several times. Purification by flash column chromatography on silica gel with CH2CI2 as eluent yielded the desired product (550 mg, 36%) as a light grey solid. ¹ H NMR (300 MHz, CDCk) 6: 8.15 (s, 1H), 7.95-7.87 (m, 2H), 7.68 (d, 7=8.5 Hz, 1H), 7.62-7.58 (m, 1H), 7.50-7.41 (m, 2H), 7.36 (dd, 7=8.5, 1.9 Hz, 1H). UPLC-ESI (m/z): 286, 288 [M+H] ⁺ .

Synthesis of Compound 75

Methyl 5-(pyridin-2-yl)benzo[b]thiophene-2-carboxylate (Nl)

Methyl 5-bromobenzo[b]thiophene-2-carboxylate (2.00 g, 7.40 mmol) and Pd(PPha)4 (852 mg, 0.74 mmol) were charged in a MW tube and flushed with Argon. Anhydrous toluene (30 mL) was added followed by 2-(tributylstannyl)pyridine (2.87 mL, 8.85 mmol). The mixture was heated to 120 °C for 3 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (eluent PE:EtOAc 9:1 to 1:1). The product-containing fractions were evaporated and the residue was recrystallized from Pet:EtOAc to give a light yellow solid (1.57 g, 79%). ¹ H-NMR (300 MHz, CDCk) 6: 8.76-8.69 (m, 1H), 8.54-8.49 (m, 1H), 8.15-8.08 (m, 2H), 7.99-7.92 (m, 1H), 7.83-7.76 (m, 2H), 7.31-7.24 (m, 1H), 3.96 (s, 3H). UPLC-ESI (m/z): 270 [M+H] ⁺ .

5-(pyridin-2-yl)benzo[b]thiophene-2-carboxylic acid (N2)

Ester Nl (1.55 g, 5.70 mmol) and LiOH monohydrate (966 mg, 23.0 mmol) were dissolved in 80 mL H2O/THF 1:1 mixture and stirred at room temperature for 16 h. 50 mL H2O was added and mixture was washed with 50 mL CH2CI2. The aqueous layer was acidified to pH 3 by addition of aq. 10% HCI. The resulting precipitate was filtered and dried to give N2 as off-white solid (1.28 g, 87%). ¹ H-NMR (300 MHz, DMSO-dg) 6: 8.82-8.71 (m, 2H), 8.28-8.08 (m, 5H), 7.61-7.53 (m, 2H). UPLC-ESI (m/z): 256 [M+H] ⁺ . Compound 75

N2 (800 mg, 3.13 mmol), HATU (1.43 g, 3.76 mmol) and 4-chloraniline hydrochloride (617 mg, 3.76 mmol) were suspended in anhydrous DMF (15 mL). To the suspension NEts (1.53 mL, 10.97 mmol) was added. The resulting red suspension was stirred at room temperature under argon for 16 h. To the red suspension was added H2O. The resulting white precipitate was filtered and recrystallized from EtOAc/PE to yield the title product as a white solid (871 mg, 76 %). ¹ H-NMR (300 MHz, DMSO-dg) 6: 10.72 (s, 1H), 8.78-8.63 (m, 2H), 8.43 (s, 1H), 8.32-8.02 (m, 3H), 7.99-7.88 (m, 1H), 7.87-7.76 (m, 2H), 7.52-7.32 (m, 3H). UPLC-ESI (m/z): 365, 367 [M+H] ⁺ . Synthesis of Compound 76

5-bromo-N-(4-chlorophenyl)thieno[2,3-b]pyridine-2-carboxa mide (N3)

5-Bromothieno[2,3-b]pyridine-2-carboxylic acid (1.00 g, 3.87 mmol), 4-chloroaniline hydrochloride (700 mg, 4.26 mmol) and HOBt-F O (300 mg, 1.94 mmol) were suspended in anhydrous CH2CI2 (20 mL). N-methyl morpholine (780 mg, 7.75 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. 3-(Ethyliminomethyleneamino)-/V,/\/-dimethylpropan-l-amine hydrochloride

(1.11 g, 5.81 mmol) was added in one portion and the resulting solution was stirred at room temperature for 16 h. The resulting suspension was evaporated under reduced pressure, and the residue was suspended in a small amount of 1,2-dichloromethane. The solids were collected by filtration and washed with minimum CH2CI2 to give the desired product as a white solid (1.14 g, 80%). ^X H NMR (300 MHz, DMSO-dg) 6: 10.81 (s, 1H), 8.79 (s, 2H), 8.31 (s, 1H), 7.83-7.77 (m, 2H), 7.49-7.41 (m, 2H).

Compound 76

N3 (1.05 g, 2.86 mmol), 4-phenylboronic acid (420 mg, 3.43 mmol), K2CO3 (470 mg, 3.43 mmol) and Pd PPhah (160 mg, 0.140 mmol) were suspended in a mixture of 1,4-dioxane (10 mL) and water (10 mL). The suspension was stirred at 100 °C for 16 h. The reaction mixture was cooled to ambient temperature and water was added. The resulting precipitate was filtered and washed with water and EtOAc several times. Crystallization from CHCU/MeOH yielded the desired product as a yellowish solid (750 mg, 72%). ^X H NMR (300 MHz, DMSO-dg) 6: 10.80 (s, 1H), 9.01 (d, 7=2.2 Hz, 1H), 8.71 (d, 7=2.2 Hz, 1H), 8.40 (s, 1H), 7.88-7.78 (m, 4H), 7.61-7.51 (m, 2H), 7.51-7.41 (m, 3H). UPLC-ESI (m/z): 365, 367

[M+H] ⁺ .

BIOLOGICAL ACTIVITY

Results

The effect of the compounds on the food intake in diet-induced obese mice over 24h is provided in Tables A and B. This animal model is recognized as being a predictive model for obesity and food intake in human as illustrated for instance by Kleinert et al (Nat Rev Endocrinol. 2018 Mar;14(3):140-162). Accordingly, the utility of the compounds of the present invention as appetite suppressant is well shown. Table A

Table B

Materials and Methods

Mice

Four-month-old male C57BL/6J mice (Charles River, Sulzfeld, Germany) were individually housed in wire- mesh hanging cages or in standard mice cages at room temperature (21° ± 1°C) and at an artificial 12-hour light/12-hour dark cycle. Animals were able to see, hear, and smell their conspecifics in neighboring cages and were not socially isolated. Water, food (60% high-fat diet, Sniff Spezialdiaten GmbH, Germany), and bedding were provided ad libitum, if not indicated differently. All procedures for mice handling and experimental interventions were according to Swiss Animal Welfare laws, approved by the "Kantonales Veterinaramt Zurich," and conform to the principles of UK regulations. Animals were adapted to novel housing situations and feeding schedules at least for 1 week. All experiments were conducted three times with saline injections before drug administration to habituate the animals to the experimental procedure. Mice compound application

Individual compounds were injected intraperitoneally as solutions or suspensions in 0.2% Tween 80 in saline (10 ml/kg), a minimum of n>8 animals were dosed per group.

Mice feeding behavior

Ad libitum fed or 16-hour-fasted mice received an intraperitoneal injection of candidate compounds within 15 min before dark onset. Food was made available at dark onset to the 16-hour-fasted mice. Food intake was measured continuously in undisturbed mice using an automated system (BioDAQ, Research Diets, NJ, USA). This system measures food hopper weight (±0.01 g) at 1-Hz resolution. The microstructure of feeding was analyzed using proprietary software (BioDAQ Monitoring Software) as follows: Absolute food hopper weight changes smaller than 0.02 g within a 5-s time interval were counted as food-seeking bouts. Absolute food hopper weight changes of 0.02 g or larger represent a meal and were summed into a single meal based on a 10-min intermeal interval.

Food intake reduction in % compared to vehicle in mice is calculated as following: 100-(mean(veh)-mean(cpd))/mean(veh)*100