DESC:FIELD OF INVENTION
The present invention relates to anti-inflammatory compounds or pharmaceutically acceptable salts, solvates, complexes, hydrates, polymorphs, racemic mixtures, optically active forms and their use for the treatment of diseases or conditions mediated by pro-inflammatory cytokines. The invention is also directed to anti-inflammatory drug compounds which are capable of treating diseases which are hard to treat with existing drug compounds. Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, novel intermediates involved in their synthesis.

BACKGROUND TO THE INVENTION
Interleukin 17 (IL 17) is a pro-inflammatory cytokine that contributes to the pathogenesis of several inflammatory diseases. The IL-17 family of cytokines consists of six isoforms (IL-17A-IL-17F) and five receptors, IL-17RA-E. IL-17A is the prototype and the best-studied member of IL-17 family, and it shares the highest sequence homology with IL-17F at 50%. IL-17A and IL-17F are known to form tightly associated homodimers, but IL-17A/F heterodimers have also been identified in vivo. IL-17RA is the prototype of IL-17R family and a shared receptor for at least IL-17A, IL-17C, IL-17E, IL-17F, and IL-17A/F signaling. IL-17RA pairs with other IL-17R members to form heterodimeric receptor complexes on the cell surface for differential IL-17 cytokine signaling. IL-17A and IL-17F signaling through the cell surface receptor complex consists of IL-17RA and IL-17RC. Both IL-17RA and IL-17RC consist of a large extracellular domain, a single-pass transmembrane helix, and an intracellular signaling motif referred to as the SEFIR domain that drives downstream signaling.
Antagonizing IL-17A/IL-17RA protein–protein interaction (PPI) was hypothesized to reduce over exaggerated inflammation in autoimmune diseases. There are several ways to block IL-17A signaling by targeting IL-17A proteins or receptors. Clinically, three monoclonal antibodies (mAbs) are already approved for different immunological diseases, secukinumab and ixekizumab target IL-17A while brodalumab targets IL- 17RA. Numerous clinical trials of anti-IL-17A and IL-17RA antibodies are currently in progress. IL-17A/IL-17RA directed biotherapeutics have achieved impressive successes in durable clinical treatment of psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis. However, IL17A has also major implications in central nervous system neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and glaucoma.
There have been three IL-17 inhibitors approved by USFDA which are monoclonal antibodies (mAbs). There is no drug approved which belongs to the small-molecule class. Some of the patents which disclose small-molecule IL-17 inhibitors are WO 2019138017, WO 2020127685, WO 2020120141, WO 2020182666, WO 2021239745, WO 2021055376, WO 2021250194, WO 2021239743, WO 2022091056, WO 2022007462 and WO 2023225664.
However, mAbs have limited applications due to non-oral administration, poor tissue penetration, lacking blood-brain barrier penetration, often long half-life times, high cost-of-good, and most importantly being applicable only to extracellular targets. For these reasons, the development of small-molecule modulators targeting IL- 17A/IL-17RA is an emerging area, which potentially could considerably widen current indication areas. Small molecules generally have a good tissue penetration with potentially higher efficacy and a tunable half-life time and are orally bioavailable facilitating patient treatment.
SUMMARY OF THE INVENTION
The invention provides compounds which are active to control IL17A mediated pathways and their use for the treatment of inflammatory diseases. The novel compounds are defined by the general formula (1) as given below. The compounds of the present invention are useful in the treatment of the human or animal body. The compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of inflammatory diseases.
PREFERRED EMBODIMENTS
The main objective of the present invention is to provide novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, novel intermediates involved in their synthesis, their polymorphs, their racemic mixtures and their optically active forms or their mixtures suitable for the treatment of inflammatory diseases.
In an embodiment is provided a process for the preparation of novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, novel intermediates involved in their synthesis, their polymorphs, their racemic mixtures and their optically active forms.
In another embodiment is provided pharmaceutical compositions comprising the novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, novel intermediates involved in their synthesis, their polymorphs, their racemic mixtures and their optically active forms having pharmaceutically acceptable carriers, solvents, diluents, binder, disintegrant, coating agent, filler, glidant, and/or other suitable excipients.
In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of inflammatory diseases, by administering a therapeutically effective & non-toxic amount of novel compounds of general formula (1) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable compositions.
In yet another embodiment is provided a method of treating inflammatory diseases using novel compounds of general formula (1) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable compositions.
DETAILED DESCRIPTION:
In a preferred embodiment, the groups referred to above may comprise of:
- the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from -CH, -CH2, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, and the like;
- the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
- the “heterocyclylalkyl” group used either alone or in combination with other radicals, is selected from groups containing an heterocyclyl radical, as defined above, attached directly to an alkyl radical, as define above;
- the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;
- the “aryl” or “aromatic” group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like;
- the “heteroaryl” or “heteroaromatic” group used either alone or in combination with other radicals, is selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;
- the “carbocycle” group used either alone or in combination with other radicals, is selected from groups as described in “cycloalkyl” or “aryl” or “aromatic”.
- The “spirocyclic ring system” when there are two positions for substitution on the same atom, for example but not limited to spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl, 2-oxa- 7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-l-azaspiro[3.3]heptanyl.
- As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 4 to 14-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms & also contains from 1 to 3 hetero atoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The term heterocycle as used in the specification includes both aromatic and non-aromatic single or fused cyclic system containing at least one heteroatom selected from N, O and S. The nitrogen and sulfur hetero atoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. A skilled person is well aware of the terms "heterocycle" or "heterocyclic system" and the present invention encompasses all such variations, alterations of definitions which are within the scope of such a skilled person. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. In a further optional embodiment, nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable bicyclic or 8 to 14 membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Also included are fused ring, bridged bicyclic heterocycles, Spiro-compounds containing, for example, the above heterocycles.
- As used herein, the term “fused rings” is intended to mean, one ring is a 4-7-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic) and comprises a 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle, or a carbocycle, each fused to a second ring. The second ring is a 5 to 7 membered monocyclic ring which is saturated, partially unsaturated, or unsaturated (aromatic), and comprises a 4-membered heterocycle, 5-membered heterocycle, 6-membered heterocycle, 7-membered heterocycle or a carbocycle.
- The term "optionally substituted," as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
- Compounds of formula (1) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of formula (1), either as single species or mixtures thereof.
- Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
- Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (1).
DETAILED DESCRIPTION:
Accordingly, the present invention relates to compounds of the general formula (1),

Wherein
Q is selected from
R2 and R3 are independently represent hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system; alternatively, R2 and R3 may combined to form 3-8 membered cycloalkyl ring, 3-8 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system. Where in, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system is substituted or unsubstituted with one or more substituents independently selected from halogen, haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O) R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
R4 is independently selected from
hydrogen, halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, -PO(R5)2, =O and -CN; C1-C6 alkyl, C4-C6 heterocycloalkyl, C3-C6 carbocycle, each of which is substituted or unsubstituted with one or more substituents independently selected from halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; C3-C10 carbocycle substituted or unsubstituted with one or more substituents independently selected from halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
n is selected from 0,1,2,3,4;
A is selected from 5 to 6 membered heteroaryl, 9 or 10 membered bicyclic heteroaryl, phenyl, each of them are substituted or unsubstituted with one or more substituents independently selected from (i), (ii) and (iii);
(i) halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(ii) C1-C10 alkyl, substituted or unsubstituted with one or more substituents independently selected from: C1-C6 alkyl, halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN; and C3-C10 carbocycle and 3-10 membered heterocycle each of which is substituted or unsubstituted with one or more substituents independently selected from halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(iii) 3-8 membered cycloalkyl ring, 3-10 membered heterocycle, bicyclic, spirocyclic substituted or unsubstituted with one or more substituents independently selected from halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN; and C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2 R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;

B is selected from (i), (ii), (iii)
(i) 5-10 membered heteroaryl ring, 5-10 membered heterocyclic ring, 3-7 membered cycloalkyl ring, each of them are optionally substituted with C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocyclic, bicyclic, spirocyclic ring, halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and –CN, -P(O)CR5; wherein, if 5-10 membered heteroaryl ring contain nitrogen in ring then nitrogen may further attached to –O;
(ii)
;
R6 and R7 are each independently selected from (a), (b), (c) and (d);
(a) Hydrogen;
(b) halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(c) C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(d) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R6 and R7 combine together to form a 3-8 membered cycloalkyl ring, 4-to 12-membered heterocycle substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R5 and R10 are independently selected at each occurrence from (I), (II) and (III);
(I) hydrogen;
(II) C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are substituted or unsubstituted with one or more substituents selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6haloalkyl -NH2, -NO2, =O, and -CN;
(III) C3-10 carbocycle and 3-10 membered heterocycle, each of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN; and C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, and –CN;
R8 and R9 are each independently selected from (a), (b), (c);
(a) Hydrogen;
(b) C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(c) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; or

R8 and R9 combined to form 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system, wherein, 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic and spirocyclic ring system is substituted or unsubstituted with one or more substituents independently selected from halogen, C1-C6 alkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; or
C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(iii)

Z1, Z2, Z3 are selected from N or C14 and wherein at least two Z1, Z2 and Z3 are C14,
Z4, Z5, Z6 are C14;
M is selected from CH or absent;
Z independently selected from C14, N;
R11 is independently selected from -NR10COR10, -NR10CON(R10)2, NR10.
R12 is independently selected from deuterium, halogen, (C1-C3) alkyl, wherein said (C1-C3) alkyl may optionally be substituted with one or more substituents independently selected from deuterium and halogen.
R13 is selected from hydrogen, (C1-C4)alkyl, and (C1-C4)cycloalkyl, wherein said
(C1-C4)cycloalkyl may optionally be substituted with one or more substituents independently selected from deuterium, halogen, cyano and hydroxy, and wherein said
(C1-C4)alkyl may optionally be substituted with one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, (C1-C4)cycloalkyl, (C1-C3)alkoxy, (C3-C4)cycloalkoxy, fluoro(C1-C4)cycloalkyl, and fluoro(C1-C3)alkoxy.
R14 is hydrogen, deuterium, halogen, cyano, (C1-C6) alkyl, (C1-C6)alkoxy, or (C3-C6)cycloalkoxy, wherein each of them is optionally substituted with one or more substituents selected from deuterium and halogen.
n1 is 0 or 1.
Particularly useful compounds may be selected from:
Example No Structure Chemical Name
1
N-(1-cyclohexyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide
2
N-(1-cyclohexyl-2-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide
3
N-(2-((4-(4-chloro-2-methyl-1-(?1-oxidaneyl)-1 ?4-pyridin-3-yl)phenyl)amino)-1-cyclohexyl-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide
4
N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide

List of Abbreviation
DMF: Dimethyl formamide
DCM: Dichloromethane
EDC : Dichloroethane
TFA: Trifluoro acetic acid
THF : Tetrahydrofurane
DIPEA: Disopropyl ethyl amine
EtOAc: Ethyl acetate
h: Hour(s)
rt : room temperature
min: Minute(s)
tRet: Retention time
HCl: Hydrochloric acid
RT: Room temperature [25-30 0C]
Cs2CO3: Cesium carbonate
K2CO3 : Potassium carbonate
K3PO4: Potassium phosphate
TEA: Triethyl amine
Instrument details
Mass spectrum was recorded on LC-MS 2010-A Shimadzu.
NMR spectrum: Bruker Avanc 400 mHz
Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.

The compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis or variation thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to those described below, where all symbols are as defined earlier.

General Scheme 1: Synthesis of compounds of general formula (1)

Amine derivative [2] on reaction with appropriate acid [3] using coupling reagent selected from DCC, EDAC, HATU, HBTU, T3P and like using base selected from TEA, DIEA, pyridine and like in a solvent selected from DCM, EDC, DMF give protected amine derivative [4]. Deprotection of protecting group (Pg) under condition selected from dioxane. HCl, TFA, Pd/C& H(2), resulted in amine compound [5]. Coupling of amine compound [6] with appropriate acid {A-COOH} using condition reported earlier gave title compound [1].
Intermediate 2 was prepared as per the procedure reported in WO2023283453, WO2020127685, WO2021055376 and as per general method reported in vogel text book of practical organic chemistry. Deuteriated analogues 3 were prepared as per the the process reported in J. Labelled. Cpd. Radiopharm, 43, 449-461, 2000.

The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (1) with suitable acids in suitable solvents by processes known in the art.
The invention is further exemplified by the following examples below, which provides some of the several preferred embodiments of the present invention. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.

Example 1: Preparation of N-(1-cyclohexyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl) amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide.

Step I: 2-Amino-2-cyclohexylacetic-2-d acid

In a 10 mL single neckround-bottomed flask was added 2-amino-2-cyclohexylacetic acid (100 mg, 0.636 mmol) in acetic-d3 acid-d (4.0 mL) or acetic acid-d (4.0 mL) at 25°C. 2-hydroxybenzaldehyde (15.54 mg, 0.127 mmol) was added in reaction mixture at 25°C. The reaction mixture was stirred at 100°C for 2 hr. After completion of reaction, the solution was concentrated under reduced pressure to dryness. The residue was treated with D2O (2.0 mL) and stirred for 15 min, then diluted with water (4.0 mL) the solution was concentrated under reduced pressure. MeOH (2.0 mL) was added in residue, solid material was filtered to get desired product. (Yield: 80 mg, 75 %). 1H NMR (D2O, 400 MHz) ? ppm: 0.55 – 0.55 (5H, m), 1.12 – 1.09 (2H, m), 1.21 (3H, bs), 1.45-1.42 (3H, m). ESI-MS: 159.3 [M+1] +.

Step : II 2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic-2-d acid

In a 100 mL two neck round-bottomed flask was added 2-amino-2-cyclohexylacetic-2-d acid (1.7 g, 10.74 mmol) in 1,4-dioxane (40 mL) and water (30 mL) at 5-10°C. Sodium carbonate (5.69 g, 53.7 mmol) and BOC-anhydride (3.74 mL, 16.12 mmol) in reaction mixture at 0-5°C, stirred at 25°C for 16 h. After completion of reaction, the mixture was quenched in water (50 mL), acidified by using dil. HCl (pH-6.0) and aq. layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired product. ESI-MS: m/z [M+H] + 159.3.

Step: III (4-(4-(2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetamido-2-d)phenyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl pivalate
In a 250 mL single neckround-bottomed flask was added 2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic-2-d acid (89 mg, 0.345 mmol) in DMF (2.0 mL) at 0-5°C. DIPEA (0.139 mL, 0.796 mmol) and HATU (121 mg, 0.319 mmol) was added in reaction mixture at 0-5°C. (4-(4-aminophenyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl pivalate (80 mg, 0.265 mmol) was added in reaction mixture and stirred at 25 °C for 1 hr. After completion of reaction, the reaction mixture was quenched in water (20 mL) and aq. layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired solid product. The crude product was purified by combiflash chromatography using ethyl acetate in hexane as mobile phase. (Yield: 45 mg, 35 %). ESI-MS: m/z [M-114] + 429.4

Step: IV (4-(4-(2-amino-2-cyclohexylacetamido-2-d) phenyl)-3,5-dimethyl-1H-pyrazol-1-yl) methyl pivalate--2,2,2-trifluoroacetaldehyde
In a 25 mL single neckround-bottomed flask was added (4-(4-(2-((tert-butoxycarbonyl) amino)-2-cyclohexylacetamido-2-d) phenyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl pivalate (40 mg, 0.074 mmol) in DCM (10 ml) at 25°C. TFA (0.043 ml, 0.554 mmol) was added in reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C for 5 hr. After completion of reaction, the solution was concentrated under reduced pressure to dryness give desired product. (Yield: 40 mg, 100 %). ESI-MS:442.5 [M+H]+ .

Step : V (4-(4-(2-cyclohexyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetamido-2-d)phenyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl pivalate
In a 10 mL single neckround-bottomed flask was added (4-(4-(2-amino-2-cyclohexylacetamido-2-d-2-d)phenyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl pivalate compound with 2,2,2-trifluoroacetaldehyde (40 mg, 0.074 mmol) in DMF (2.0 mL) at 0-5°C. DIPEA (0.078 mL, 0.445 mmol) and HATU (33.8 mg, 0.089 mmol) was added in reaction mixture at 0-5°C, stirred for 15 min. 1-isopropyl-1H-pyrazole-5-carboxylic acid (11.43 mg, 0.074 mmol) was added in reaction mixture and stirred at 25 °C for 1 hr. After completion of reaction, the reaction mixture was quenched in water (20 ml) and aq. layer was extracted with EtOAc. Organic layers were washed with water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford desired solid product. The crude product was purified by combiflash chromatography using ethyl acetate in hexane as mobile phase. (Yield: 30 mg, 70 %). LC-MS: m/z [M+H] + 579.8.

Step : VI N-(1-cyclohexyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide
In a 10 mL single neckround-bottomed flask was added (4-(4-(2-cyclohexyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetamido-2-d-2-d)phenyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl pivalate (30 mg, 0.052 mmol) in water (1.0 mL) and MeOH (1.0 mL) at 0-5°C. NaOH (8.31 mg, 0.208 mmol) was added in reaction mixture at 0-5°C and stirred for 1 hr. After completion of reaction, solid was filtered off and washed with water (1.0 ml). (Yield: 16 mg, 66 %). 1H NMR (DMSO-d6, 400 MHz) ? ppm: 12.23 (1H, bs), 10.26 (1H, s), 8.50 (1H, s), 7.65 (2H, d, J=8.4 Hz), 7.50 (1H, d, J=1.6 Hz), 7.22 (2H, d, J=8.8 Hz), 6.96 (1H, d, J=2.0 Hz), 5.44-5.37 (1H, m), 2.17 (6H, s), 1.86-1.84 (2H, m), 1.72-1.70 (2H, m), 1.61-1.59 (2H, m), 1.38-1.34 (6H, m), 1.23-1.17 (4H, m), 1.07-1.02 (1H, m). ESI-MS: m/z [M+H] + 464.34.
Example 2: Preparation of N-(1-cyclohexyl-2-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide.

N-(1-cyclohexyl-2-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide prepared as per the procedure reported for example 1 but using 2-(4-amino-3-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide in step II example 1. The title compound was characterised by spectral analysis. 1H NMR (DMSO- d6, 400 MHz) ? ppm: 9.90 (1H, s), 8.43 (1H, s), 7.74 (1H, d, J=8.4 Hz), 7.49 (1H, d, J=1.6 Hz), 7.15 - 7.11 (1H, m), 7.05-7.04 (1H, m), 6.93 (1H, d, J=1.6 Hz), 5.39 (1H, t, J=6.8 Hz), 4.19-4.18 (3H, m), 2.99 (2H, s), 1.72-1.65 (2H, m), 1.63-1.55 (2H, m), 1.55-1.51 (2H, m), 1.38-1.34 (6H, m), 1.31-1.27 (3H, m), 1.241.18 (5H, m), 1.17-1.06 (2H, m). ESI-MS: 555.31 [M+H] +.
Example 3: Preparation of N-(2-((4-(4-chloro-2-methyl-1-(?1-oxidaneyl)-1 ?4-pyridin-3-yl)phenyl)amino)-1-cyclohexyl-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide.

N-(2-((4-(4-chloro-2-methyl-1-(?1-oxidaneyl)-1 ?4-pyridin-3-yl)phenyl)amino)-1-cyclohexyl-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide prepared as per the procedure reported for example 1 but using 4-(4-chloro-2-methyl-1-( ?1-oxidaneyl)-1 ?4-pyridin-3-yl)aniline in step II example 1. The title compound was characterised by spectral analysis. 1H NMR (DMSO- d6, 400 MHz) ? ppm: 10.41 (1H, s), 8.54 (1H, s), 8.32 (1H, d, J=5.6 Hz), 7.80-7.78 (2H, m), 7.76 (1H, d, J=5.6 Hz), 7.55-7.50 (1H, m), 7.25 (2H, d, J=7.2 Hz), 6.97 (1H, d, J=1.6 Hz), 5.40-5.38 (1H, m), 1.87-1.85 (2H, m), 1.73-1.69 (2H, m), 1.62-1.58 (2H, m), 1.38 (6H, s), 1.26-1.22 (3H, m), 1.20-1.17 (1H, m), 0.86-0.85 (1H, m). ESI-MS: 511.4 [M+H] +
Example 4: N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide.

N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide prepared as per the procedure reported for example 1 but using 2-(4-amino-2-(dimethylphosphoryl)-5-fluorophenyl)-N-methyl-N-(2,2,2-trifluoroethyl)propanamide in step II example 1. The title compound was characterised by spectral analysis. ESI-MS: 631.30 [M+H] + 1H NMR (DMSO- d6, 400 MHz) ? ppm: 10.20 (1H, br s), 8.45 (1H, s), 8.20 - 8.00 (1H, m), 7.50 (1H, s), 7.15-7.00 (1H, m), 6.95 (1H, s), 5.62-5.60 (1H, m), 5.43-5.37 (1H, m), 4.35-4.05 (2H, m), 3.07-3.05 (2H, m), 1.86-1.78 (2H, m), 1.75-1.69 (6H, m), 1.65-1.50 (2H, m), 1.37-1.32 (9H, m), 1.29-1.23 (5H, m), 1.18-1.14 (3H, m).

Activity data:
Biological Activity
To evaluate potential inhibitor of IL- 17A, Human IL-17A/IL-17RA HTRF binding kit (Cisbio, cat no: 64BDIL17PEG) was used, which measures interaction between IL-17A and it's receptor, IL-17RA. In the presence of an IL-17A inhibitor, this interaction is perturbed. NCEs were routinely screened using this kit according to the manufacturer's protocol. Briefly, 4 uL of Tag1-IL17A and 2uL of increasing concentration of 10X (with a final 1% DMSO concentration) compound (1nM to 10 uM) were pre-incubated for 1 hr at room temperature in low volume white 384 well plate. After that, 4 uL of Tag2-IL17RA were added in each well. Finally, 10 uL of premix detection reagent, which contains 1X each of anti-Tag1 EU cryptate (donor) and anti-Tag2 XL665 antibody (acceptor), were added in each well and plate was incubated in dark for 24 hrs at room temperature. Next day, plate was read in Hidex multimode reader with an excitation wave length of 330 nm and dual emissions wave length of 665 and 620 nm.
% inhibition of binding interaction of compounds was calculated from the HTRF ratio, with respect to vehicle, which represents 100% binding. For IC50 determination, % inhibition of binding interaction was fed in Graph Pad prism using a four parameter non linear regression analysis.
The exemplified compounds belonging to Formula I demonstrated potent IL17A inhibitory potency.
Example No IC(50) nM
1 128
2 813
3 81
4 836

The novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention are useful as a medicament for the inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis and suitable for humans and other warm-blooded animals, and may be administered either by oral, topical or parenteral administration.
The quantity of the active component, that is, The novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention and unit dosage form thereof may be varied or adjusted widely depending upon several factors such as the particular application method, the potency of the particular compound and the desired concentration.

Use of the novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention for the treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.

A method of treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis by administering to a subject in need thereof a therapeutically effective amount of the novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures of the present invention.

The invention relates to IL-17 inhibitor for inflammatory conditions, such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.

,CLAIMS:We claim:

1. A novel compounds of general formula (1), their suitable pharmaceutically acceptable salts, their solvates, their hydrates, their stereoisomers, their polymorphs, their racemic mixtures and their optically active forms or their mixtures,

wherein
Q is selected from ;
R2 and R3 are selected from hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system; alternatively, R2 and R3 combined to form 3-8 membered cycloalkyl ring, 3-8 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system; wherein, C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocycloalkyl, C5-C6 heteroaryl, aryl, bicyclic, spirocyclic ring system is substituted or unsubstituted with one or more substituents independently selected from halogen, haloalkyl, C1-C6 alkyl, C3-C6 cycloalkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O) R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
R4 is selected from
hydrogen, halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, -PO(R5)2, =O and -CN; C1-C6 alkyl, C4-C6 heterocycloalkyl, C3-C6 carbocycle, each of which is substituted or unsubstituted with one or more substituents independently selected from halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; C3-C10 carbocycle substituted or unsubstituted with one or more substituents independently selected from halogen, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
n is selected from 0,1,2,3,4;
A is selected from 5 to 6 membered heteroaryl, 9 or 10 membered bicyclic heteroaryl, phenyl, each of them are substituted or unsubstituted with one or more substituents independently selected from (i), (ii) and (iii);
(i) halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(ii) C1-C10 alkyl, substituted or unsubstituted with one or more substituents independently selected from: C1-C6 alkyl, halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN; and C3-C10 carbocycle and 3-10 membered heterocycle each of which is substituted or unsubstituted with one or more substituents independently selected from halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(iii) 3-8 membered cycloalkyl ring, 3-10 membered heterocycle, bicyclic, spirocyclic substituted or unsubstituted with one or more substituents independently selected from halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =,O and -CN; and C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O) R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2 R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
B is selected from (i), (ii), (iii)
(i) 5-10 membered heteroaryl ring, 5-10 membered heterocyclic ring, 3-7 membered cycloalkyl ring, each of them are substituted or unsubstituted with C1-C6 alkyl, C3-C7 cycloalkyl, C4-C7 heterocyclic, bicyclic, spirocyclic ring, halogen, deuterium, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)O R5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and –CN, -P(O)CR5; wherein, if 5-10 membered heteroaryl ring contain nitrogen in ring then nitrogen may further attached to –O;
(ii)
;
R6 and R7 are each independently selected from (a), (b), (c) and (d);
(a) hydrogen;
(b) halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=N R10)R10, -NO2, - CN;
(c) C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(d) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R6 and R7 combine together to form a 3-8 membered cycloalkyl ring, 4-to 12-membered heterocycle substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
R5 and R10 are selected at each occurrence from (I), (II) and (III);
(I) hydrogen;
(II) C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are substituted or unsubstituted with one or more substituents selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6haloalkyl -NH2, -NO2, =O, and -CN;
(III) C3-10 carbocycle and 3-10 membered heterocycle, each of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OH, C1-C6 haloalkyl, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, -CN; and C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from halogen, -OH, -OC1-C6 alkyl, -OC1-C6 haloalkyl -NH2, -NO2, =O, and –CN;
R8 and R9 are each independently selected from (a), (b), (c);
(a) Hydrogen;
(b) C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, -OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O)R10, -S(O)2R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN;
(c) C3-10 carbocycle and 3- to 10-membered heterocycle any of which is substituted or unsubstituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; C1-6 alkyl substituted or unsubstituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -C(O)R10, -C(O)NH2, -C(O)-O-C1-6-alkyl, - OC(O)R10, -OC(O)N(R10)2, -N(R10)C(O)R10, -N(R10)C(O)O R10, - N(R10)C(O)N(R10)2, -N(R10)S(O)2(R10), -S(O) R10, -S(O)2 R10, -S(O)2N(R10)2, -S(=O)(=NR10)R10, -NO2, - CN; or

R8 and R9 combined to form 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic or spirocyclic ring system, wherein, 3-8 membered cycloalkyl ring, 4-12 membered heterocyclic ring, aryl, bicyclic and spirocyclic ring system is substituted or unsubstituted with one or more substituents independently selected from halogen, C1-C6 alkyl, -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O) R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN; or
C1-C6 alkyl substituted or unsubstituted with one or more substituents independently selected from -OR5, -SR5, -N(R5)2, -C(O)R5, -C(O)OR5, -OC(O)R5, -OC(O)N(R5)2, -C(O)N(R5)2, -N(R5)C(O)R5, -N(R5)C(O)OR5, -N(R5)C(O)N(R5)2, -N(R5)S(O)2(R5), -S(O)R5, -S(O)2R5, -S(O)2N(R5)2, -S(=O)(=NR5)R5, -NO2, =O and -CN;
(iii)

Z1, Z2, Z3 are selected from N or C14 and wherein at least two Z1, Z2 and Z3 are C14; Z4, Z5, Z6 are C14;
M is selected from CH or absent;
Z is selected from C14, N;
R11 is selected from -NR10COR10, -NR10CON(R10)2, NR10;
R12 is selected from deuterium, halogen, (C1-C3) alkyl, wherein said (C1-C3) alkyl substituted or unsubstituted with one or more substituents independently selected from deuterium and halogen;
R13 is selected from hydrogen, (C1-C4)alkyl, and (C1-C4)cycloalkyl, wherein said
(C1-C4)cycloalkyl substituted or unsubstituted with one or more substituents independently selected from deuterium, halogen, cyano and hydroxy, and wherein said
(C1-C4)alkyl substituted or unsubstituted with one or more substituents independently selected from deuterium, halogen, cyano, hydroxy, (C1-C4)cycloalkyl, (C1-C3)alkoxy, (C3-C4)cycloalkoxy, fluoro(C1-C4)cycloalkyl, and fluoro(C1-C3)alkoxy;
R14 is hydrogen, deuterium, halogen, cyano, (C1-C6) alkyl, (C1-C6)alkoxy, or (C3-C6)cycloalkoxy, wherein each of them is substituted or unsubstituted with one or more substituents selected from deuterium and halogen;
n1 is 0 or 1.

2. A novel compounds of general formula (1) as claimed in claim 1,
wherein, A is selected from 5 to 6 membered heteroaryl;
R2 and R3 combined to form 3-8 membered cycloalkyl ring;
Q is selected from ;
n is 1, 2;
R4 is selected from hydrogen, halogen, -PO(R5)2; R5 is selected from hydrogen;
B is selected from
(i) 5-10 membered heteroaryl ring; wherein, if 5-10 membered heteroaryl ring contain nitrogen in ring then nitrogen may further attached to –O;
(ii) ;
R6 and R7 are selected from hydrogen, C1-C6 alkyl;
M is absent;
R8 and R9 are selected from C1-C6 alkyl which is substituted or unsubstituted with one or more substituents independently selected from halogen.

3. Compounds of the formula (1) as claimed in claim 1:
N-(1-cyclohexyl-2-((4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-(1-cyclohexyl-2-((2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-(2-((4-(4-chloro-2-methyl-1-(?1-oxidaneyl)-1 ?4-pyridin-3-yl)phenyl)amino)-1-cyclohexyl-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide;
N-(1-cyclohexyl-2-((5-(dimethylphosphoryl)-2-fluoro-4-(1-(methyl(2,2,2-trifluoroethyl)amino)-1-oxopropan-2-yl)phenyl)amino)-2-oxoethyl-1-d)-1-isopropyl-1H-pyrazole-5-carboxamide.

4. Use of the novel compounds of general formula (1) as claimed in claim 1 for the treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.

5. Method of treating inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis comprising administering to a subject in need thereof a therapeutically effective amount of the novel compounds of general formula (1) as claimed in claim 1 or its suitable pharmaceutical composition.

6. Use of the novel compounds of general formula (1) as claimed in claim 1 in the manufacture of medicament for the treatment of inflammatory conditions such as psoriasis, asthma, psoriatic arthritis or rheumatoid arthritis.