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WO2025077732A1 - Nouveaux inhibiteurs d'interleukine-17 - Google Patents

Nouveaux inhibiteurs d'interleukine-17 Download PDF

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Publication number
WO2025077732A1
WO2025077732A1 PCT/CN2024/123669 CN2024123669W WO2025077732A1 WO 2025077732 A1 WO2025077732 A1 WO 2025077732A1 CN 2024123669 W CN2024123669 W CN 2024123669W WO 2025077732 A1 WO2025077732 A1 WO 2025077732A1
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Prior art keywords
alkyl
cycloalkyl
heterocyclyl
substituents
haloalkyl
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PCT/CN2024/123669
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English (en)
Inventor
Tianan Fang
Chang Bai
Xiaohui Hu
Jing Su
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Foshan Ionova Biotherapeutics Co Inc
Guangdong Touchstone Translational Research Institute Co Ltd
Shenzhen Ionova Life Science Co Ltd
Original Assignee
Foshan Ionova Biotherapeutics Co Inc
Guangdong Touchstone Translational Research Institute Co Ltd
Shenzhen Ionova Life Science Co Ltd
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Publication of WO2025077732A1 publication Critical patent/WO2025077732A1/fr
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    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Cytokines are small cell-signaling protein molecules secreted by numerous cells (e.g., lymphocytes, macrophages, natural killer (NK) cells, mast cells, and stromal cells) , and act as important mediators associated with the communication network of the immune system (Adv Sci (Weinh) . 2021 Aug; 8 (15) : 2004433) .
  • Interleukin 17 has emerged as a key cytokine that plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases.
  • the IL-17 family consists of six major isoforms: IL-17A (usually refers to IL-17) , IL-17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F.
  • IL-17A is the first member discovered and the most widely investigated cytokine, which plays a key pathological role in many inflammatory and autoimmune diseases.
  • IL-17A can be produced by a variety of immune and inflammatory cells, especially Th17 cells, a subtype of CD4+T cells.
  • IL-17 can synergize with other cytokines such as TNF- ⁇ , IL-1 ⁇ , IL-22, IFN- ⁇ , and GM-CSF to enhance production of inflammatory mediators like IL-6 and IL-8 (Front. Immunol., Feb 4, 2021; Sec. Inflammation, Vol. 11, 2020) .
  • cytokines such as TNF- ⁇ , IL-1 ⁇ , IL-22, IFN- ⁇ , and GM-CSF.
  • IL-17A The proinflammatory activities of IL-17 are key in anti-microbial protection of the host, however, if dysregulated, excess production of IL-17 is associated with different immunopathological conditions, inflammatory and autoimmune diseases, and cancer progression (Trends Immunol. (2017) 38: 310-22) .
  • IL-17A levels are elevated in various inflammatory conditions, including sepsis, pneumonia, systemic lupus erythematosus, rheumatoid arthritis, allograft rejection, and cancer.
  • Studies have indicated that IL-17A is a promising therapeutic target (Front. Immunol., 28 July 2020, Sec. Cytokines and Soluble Mediators in Immunity, Volume 11-2020) .
  • IL-17 blockade Positive effects of IL-17 blockade have been shown in clinical trials.
  • IL-17A e.g., ixekizumab and secukinumab
  • IL-17RA IL-17A receptor
  • numerous anti-IL-17A and/or IL-17RA antibodies are currently in clinical trials.
  • these mAbs alone or in combination, would be investigated for potential treatment of autoimmune diseases and cancer (International Immunopharmacology, Volume 123, October 2023, 110757) .
  • the present invention provides a novel class of orally bioavailable, readily absorbable, and efficacious small molecules as IL-17A modulators for treatment of inflammatory diseases and other IL-17A associated conditions including, but not limited to, psoriasis, psoriatic arthritis, asthma, and multiple sclerosis.
  • the present invention relates to a compound of Formula (I) .
  • Such compounds are potent interleukin-17A (IL-17A) inhibitors, and useful in the treatment of an inflammatory disease and other IL-17A associated conditions and diseases.
  • IL-17A potent interleukin-17A
  • the present invention provides a compound of Formula (I) , or a pharmaceutically acceptable salt, a stereoisomer, or a tautomer thereof.
  • A is cycloalkyl, heterocyclyl, aryl, heteroaryl, -NH-cycloalkyl, -NH-heterocyclyl, -NH-alkyl, -O-heterocyclyl, -O-alkyl, or -O-cycloalkyl; and A is optionally substituted with one or more substituents each of which is independently halogen, alkyl, haloalkyl, C 3-10 cycloalkyl, 3-to 10-membered heterocyclyl, -OR 9 , -SR 9 , -N (R 9 ) 2 , -C (O) R 9 , -C (O) N (R 9 ) 2 , -N (R 9 ) C (O) R 9 , -N (R 9 ) S (O) 2 R 9 , -C (O) OR 9 , -OC (O) R 9 , -S (O) R 9 , -S (O) 2
  • ring L is aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein a ring-forming carbon atom of the monocyclic or bicyclic aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with oxo to form a carbonyl group; and ring L is optionally substituted with one or more R 5 ;
  • heterocyclyl or heteroaryl in each occurrence has at least one ring-forming carbon atom and 1 to 4 ring-forming heteroatoms each of which is independently N, O or S;
  • R 17 is H or alkyl
  • n 0, 1, or 2;
  • n 0, 1, or 2;
  • each q is independently 0, 1 or 2;
  • R 1 and R 2 are both absent, and the carbon atom to which both R 1 and R 2 are bonded is substituted with oxo to form a carbonyl group;
  • R 3 and R 4 are both absent, and the carbon atom to which both R 3 and R 4 are bonded is substituted with oxo to form a carbonyl group;
  • p 0, 1, 2, or 3;
  • R 7 is H, alkyl, -OR 26 , -N (R 26 ) (R 27 ) , -N (R 26 ) C (O) R 27 , -N (R 26 ) C (O) OR 27 , -N (R 26 ) C (O) N (R 27 ) (R 28 ) , -N (R 26 ) S (O) 2 N (R 27 ) (R 28 ) , or -N (R 26 ) S (O) 2 (R 27 ) ;
  • R 11 , R 12 , R 15 and R 16 are each independently H, halogen, haloalkyl, -OR 18 , -SR 18 , -NR 18 R 18’ , -C (O) R 18 , -C (O) OR 18 , -OC (O) R 18 , -OC (O) NR 18 R 18’ , -C (O) NR 18 R 18’ , -N (R 18 ) C (O) R 18 , -N (R 18 ) C (O) OR 18 , -N (R 18 ) C (O) NR 18 R 18’ , -N (R 18 ) S (O) 2 (R 18 ) , -S (O) R 18 , -S (O) 2 R 18 , -S (O) 2 NR 18 R 18’ , -NO 2 , -CN, C 1-6 alkyl, cycloalkyl, or heterocyclyl; wherein the C 1-6 alky
  • R 18 and R 18’ together with the nitrogen atom to which both R 18 and R 18’ are bonded, form an optionally substituted monocyclic, spiro-bicyclic, or fused-bicyclic heterocyclyl;
  • R 11 and R 12 together with the carbon atom to which both R 11 and R 12 are bonded, form an optionally substituted cycloalkyl or heterocyclyl;
  • R 13 and R 14 are each independently H, alkyl, halo, haloalkyl, C 3-10 cycloalkyl, or 3-to 10-membered heterocyclyl, wherein the alkyl, C 3-10 cycloalkyl and 3-to 10-membered heterocyclyl are each optionally substituted with one or more substituents each of which is independently halogen, alkyl, -OR 15 , -SR 15 , -N (R 15 ) 2 , -C (O) R 15 , -C (O) NH 2 , -C (O) -O-C 1-6 -alkyl, -OC (O) R 15 , -OC (O) N (R 15 ) 2, -N (R 15 ) C (O) R 15 , -N (R 15 ) C (O) OR 15 , -N (R 15 ) C (O) N (R 15 ) 2 , -N (R 15 ) S (O) 2 (R
  • R 13 and R 14 together with the atom to which both R 13 and R 14 are bonded, form a monocyclic, spiro-bicyclic or fused-bicyclic heterocycle optionally substituted with one or more substituents each of which is independently halogen, C 1-6 alkyl, -OR 16 , -SR 16 , -N (R 16 ) 2 , -C (O) R 16 , -C (O) OR 16 , -OC (O) R 16 , -OC (O) N (R 16 ) 2, -C (O) N (R 16 ) 2 , -N (R 16 ) C (O) R 16 , -N (R 16 ) C (O) OR 16 , -N (R 16 ) C (O) N (R 16 ) 2 , -N (R 16 ) S (O) 2 (R 16 ) , -S (O) R 16 , -S (O) 2 R 16 ,
  • Examples of L include, but are not limited to, the following:
  • the compound is of Formula (V) , (VI) or (XI) as follows:
  • X is O or NR 17 ;
  • R 17 is H or alkyl
  • ring L is aryl or heteroaryl; and ring L is optionally substituted with one or more R 5 ;
  • p 0, 1, 2, or 3;
  • heterocyclyl or heteroaryl in each occurrence has at least one ring-forming carbon atom and 1 to 4 ring-forming heteroatoms each of which is independently N, O or S;
  • each q is independently 0, 1 or 2;
  • R 11 , R 12 , R 15 and R 16 are each independently H, halogen, haloalkyl, -OR 18 , -SR 18 , -NR 18 R 18’ , -C (O) R 18 , -C (O) OR 18 , -OC (O) R 18 , -OC (O) NR 18 R 18’ , -C (O) NR 18 R 18’ , -N (R 18 ) C (O) R 18 , -N (R 18 ) C (O) OR 18 , -N (R 18 ) C (O) NR 18 R 18’ , -N (R 18 ) S (O) 2 (R 18 ) , -S (O) R 18 , -S (O) 2 R 18 , -S (O) 2 NR 18 R 18’ , -NO 2 , -CN, C 1-6 alkyl, cycloalkyl, or heterocyclyl; wherein the C 1-6 alky
  • R 11 and R 12 together with the carbon atom to which both R 11 and R 12 are bonded, form a monocyclic, spiro-bicyclic, fused-bicyclic cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, -OR 18 , -SR 18 , -NR 18 R 18’ , -C (O) R 18 , -C (O) OR 18 , -OC (O) R 18 , -OC (O) NR 18 R 18’ , -C (O) NR 18 R 18’ , -N (R 18 ) C (O) R 18 , -N (R 18 ) C (O) OR 18 , -N (R 18 ) C (O) NR 18 R 18’ , -N (R 18 ) S (O) 2 (R 18 ) , -S (O) R 18
  • R 18 and R 18’ together with the nitrogen atom to which both R 18 and R 18’ are bonded, form an optionally substituted monocyclic, spiro-bicyclic, or fused-bicyclic heterocyclyl;
  • R 13 and R 14 are each independently H, alkyl, halo, haloalkyl, C 3-10 cycloalkyl, or 3-to 10-membered heterocyclyl, wherein the alkyl, C 3-10 cycloalkyl and 3-to 10-membered heterocyclyl are each optionally substituted with one or more substituents each of which is independently halogen, alkyl, -OR 15 , -SR 15 , -N (R 15 ) 2 , -C (O) R 15 , -C (O) NH 2 , -C (O) -O-C 1-6 -alkyl, -OC (O) R 15 , -OC (O) N (R 15 ) 2, -N (R 15 ) C (O) R 15 , -N (R 15 ) C (O) OR 15 , -N (R 15 ) C (O) N (R 15 ) 2 , -N (R 15 ) S (O) 2 (R
  • R 13 and R 14 together with the atom to which both R 13 and R 14 are bonded, form a monocyclic, spiro-bicyclic or fused-bicyclic heterocycle, optionally substituted with one or more substituents each of which is independently halogen, C 1-6 alkyl, -OR 16 , -SR 16 , -N (R 16 ) 2 , -C (O) R 16 , -C (O) OR 16 , -OC (O) R 16 , -OC (O) N (R 16 ) 2, -C (O) N (R 16 ) 2 , -N (R 16 ) C (O) R 16 , -N (R 16 ) C (O) OR 16 , -N (R 16 ) C (O) N (R 16 ) 2 , -N (R 16 ) S (O) 2 (R 16 ) , -S (O) R 16 , -S (O) 2 R 16 ,
  • B 1 is B 2 is H; each R 34 is independently H, alkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, -CN, -alk-CN, -NR 18 R 18’ , -alk-NR 18 R 18’ , halogen or haloalkyl; and q is 0, 1 or 2.
  • the compound is of Formula (V-a) , (V-b) , (VI-a) , (VI-b) , (XI-a) or (XI-b) as follows:
  • R 34 is H, alkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, -CN, -alk-CN, -NR 18 R 18’ , -alk-NR 18 R 18’ , halogen or haloalkyl;
  • q 0, 1 or 2;
  • X is O or NR 17 ;
  • R 17 is H or alkyl
  • a 1 , A 2 , R 5 , p, L and Y are the same as defined above.
  • L is N
  • Y is
  • M is a monocyclic, spiro-bicyclic, fused-bicyclic cycloalkyl or heterocyclyl;
  • M’ is a monocyclic, spiro-bicyclic, fused-bicyclic heterocyclyl
  • R 35 is halogen, haloalkyl, -OR 18 , -SR 18 , -NR 18 R 18’ , -C (O) R 18 , -C (O) OR 18 , -OC (O) R 18 , -OC (O) NR 18 R 18’ , -C (O) NR 18 R 18’ , -N (R 18 ) C (O) R 18 , -N (R 18 ) C (O) OR 18 , -N (R 18 ) C (O) NR 18 R 18’ , -N (R 18 ) S (O) 2 (R 18 ) , -S (O) R 18 , -S (O) 2 R 18 , -S (O) 2 NR 18 R 18’ , -NO 2 , -CN, C 1-6 alkyl, cycloalkyl, or heterocyclyl; wherein the C 1-6 alkyl, cycloalkyl and heterocyclyl are each
  • q 0, 1, or 2;
  • R 11 , R 12 , R 13 and R 14 are the same as defined above.
  • the compound is of Formula (V-c) , Formula (V-d) , Formula (VI-c) , Formula (VI-d) , Formula (XI-c) or Formula (XI-d) as follows:
  • the compound is of Formula (V-e)
  • M is a monocyclic, spiro-bicyclic, fused-bicyclic cycloalkyl or heterocyclyl;
  • M’ is a monocyclic, spiro-bicyclic, fused-bicyclic heterocyclyl
  • R 35 is halogen, haloalkyl, -OR 18 , -SR 18 , -NR 18 R 18’ , -C (O) R 18 , -C (O) OR 18 , -OC (O) R 18 , -OC (O) NR 18 R 18’ , -C (O) NR 18 R 18’ , -N (R 18 ) C (O) R 18 , -N (R 18 ) C (O) OR 18 , -N (R 18 ) C (O) NR 18 R 18’ , -N (R 18 ) S (O) 2 (R 18 ) , -S (O) R 18 , -S (O) 2 R 18 , -S (O) 2 NR 18 R 18’ , -NO 2 , -CN, C 1-6 alkyl, cycloalkyl, or heterocyclyl; wherein the C 1-6 alkyl, cycloalkyl and heterocyclyl are each
  • q 0, 1, or 2.
  • the compound is of Formula (VI-e) :
  • R 1 is haloalkyl
  • the compound is of Formula (XI-e) :
  • Examples of A include, but are not limited to, the following:
  • A is optionally substituted.
  • Exemplary compounds of Formula (I) include, but are not limited to, the following:
  • Another aspect of this invention includes a pharmaceutical composition, each including a therapeutically effective amount of a compound as described, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a stereoisomer thereof, in admixture with one or more physiologically acceptable carriers or excipients.
  • such pharmaceutical composition may include a second therapeutic agent.
  • Yet still another aspect of this invention provides a method for inhibiting IL-17A in a subject in need thereof, comprising administering to the subject an effective amount of the compound or the pharmaceutical composition as described.
  • Yet still another aspect of this invention provides a method for treating an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of the compound or the pharmaceutical composition as described.
  • the inflammatory disease or condition is mediated by overexpression of IL-17A.
  • inflammatory disease examples include, but are not limited to, ankylosing spondylitis, aspsoriatic arthritis, erythrodermic psoriasis, guttate psoriasis, hidradenitis suppurutiva, inverse psoriasis, non-infectious uveitis, palmoplantar psoriasis, plaque psoriasis, pustular psoriasis, rheumatoid arthritis, or spondyloarthritis.
  • a subject is a mammal, preferably, a human being.
  • Yet still another aspect of this invention provides use of the compounds as described for the manufacture of a medicament for treating the disorders mediated by overexpression of IL-17A.
  • references to Formula (I) in all sections of this document include references to all other sub-formula, sub-groups, preferences, embodiments and examples as defined herein.
  • the term “or” is meant to include both “and” and “or” . In other words, the term “or” may also be replaced with “and/or” .
  • a dashed line represents a single bond or a double bond as required to complete the valences of the atoms being linked by the bond.
  • the term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond.
  • saturated refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
  • alkyl by itself or as part of another substituent refers to a linear (i.e., unbranched or straight) or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having the stated number of carbon atoms (e.g., C 1 -C 10 or C 1-10 alkyl) .
  • saturated linear or straight alkyl includes, but not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl includes, but not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylbutyl, and the like.
  • the alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, an alkyl group is optionally substituted by one or more substituents.
  • alkyl When any H in “alkyl” is replaced with deuterium (D) , the alkyl is a “deuterated alkyl” .
  • alkylene by itself or as part of another molecule means a divalent radical derived from an alkane, which can be a straight chain or branched chain.
  • the prefixes e.g., C 1-4 , C 1-7 , C 1-20 , C 2-7 , C 3-7 , etc.
  • C 1-4 alkylene, ” as used herein, refers to an alkylene group having from 1 to 4 carbon atoms.
  • linear C 1-8 alkylene groups include, but are not limited to, - (CH 2 ) n -where n is an integer from 1 to 7, for example, -CH 2 -, -CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 -.
  • Examples of branched C 1-7 alkylene groups include, but are not limited to, -CH(CH 3 ) -, -CH (CH 3 ) CH 2 -, -CH (CH 3 ) CH 2 CH 2 -, -CH (CH 3 ) CH 2 CH 2 CH 2 -, -CH (CH 3 ) CH 2 CH 2 -, -CH 2 CH (CH 3 ) CH 2 -, -CH 2 CH (CH 3 ) CH 2 -, -CH (CH 2 CH 3 ) CH 2 -, and -CH 2 CH (CH 2 CH 3 ) CH 2 -.
  • alkenyl by itself or as part of another substituent refers to an unsaturated branched or straight-chain having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond (s) .
  • Typical alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.
  • alkynyl by itself or as part of another substituent refers to carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof.
  • alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
  • cycloalkyl by itself or as part of another substituent refers to a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • the term cycloalkyl includes monocyclic cycloalkyl, bicyclic cycloalkyl, polycyclic cycloalkyl, bridged cycloalkyl, fused cycloalkyl, and spiro cycloalkyl groups.
  • a bridged cycloalkyl the rings share at least two common non-adjacent atoms.
  • fused bicyclic cycloalkyl two rings share a covalent bond.
  • spirocyclic cycloalkyl group one atom is common to two different rings.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, wherein at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl, ” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • heterocycle refers to a group derived from a monocyclic, bridged bicyclic, fused bicyclic, spirocyclic or polycyclic moiety comprising at least one nonaromatic ring comprising one or more ring-forming heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined) .
  • the heterocyclyl can be saturated or partially unsaturated.
  • a heterocyclyl may comprises 1 to 4 heteroatoms as ring members.
  • heterocyclyl groups of the present disclosure can be attached to the parent molecular moiety through a carbon atom or a heteroatom in the group.
  • the term is inclusive of, but not limited to, “heterocycloalkyl” , “heteroaryl” , “bicyclic heterocycle” and “polycyclic heterocycle” .
  • Ring refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls) , heterocycles (e.g., heteroaryls and non-aromatic heterocycles) , aromatics (e.g., aryls and heteroaryls) , and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles) . Rings can be optionally substituted. Rings can be monocyclic or polycyclic.
  • halo refers to fluorine (fluoro, -F) , chlorine (chloro, -Cl) , bromine (bromo, -Br) , or iodine (iodo, -I) .
  • haloalkyl refers to alkyl as defined above in which one or more of the hydrogen atoms have been replaced with a halogen independently selected from fluoro, chloro, bromo, and iodo.
  • fluoroalkyl means alkyl as defined above wherein one or more hydrogen atoms have been replaced by fluoro atoms.
  • a haloalkyl can include as many as chemically possible halo atoms as substituents on the alkyl group.
  • fluoroethyl can be -CH 2 CF 3 , -CHF-CH 3 , or -CH 2 CH 2 F.
  • hydrogen includes its isotopes of deuterium (D or 2 H) and tritium ( 3 H) , meaning a or any hydrogen atom in the compounds of this invention can be replaced with either deuterium (D or 2H) and tritium (3H) .
  • alkoxy refers to a saturated straight or branched hydrocarbon linked to an oxygen atom.
  • Representative saturated straight chain alkoxys include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hextoxy, and the like; while saturated branched alkoxys include isopropoxyl, sec-butoxy, isobutoxy, tert-butoxy, isopentoxy, and the like.
  • Cyclic alkoxy are referred to herein as a “cycloalkoxy” .
  • C1-4alkoxy refers to an alkyl with 1, 2, 3, or 4 carbon atoms. Alkoxy can be linked to a molecule by one or two attachment points.
  • alkoxyalkyl refers to an alkyl group substituted with one, two, or three alkoxy groups.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthyl and anthracenyl. The “aryl” group can be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups examples, without limitation, of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, carbazole, benzimidazole, benzoxazole, benzthiazole, indazole and quinazoline.
  • the heteroaryl group may be substituted or unsubstituted.
  • arylene refers to a bidentate moiety obtained by removing two hydrogen atoms, one from each of two different aromatic ring atoms of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified) .
  • each ring has from 5 to 7 ring atoms.
  • hydroxyl or “hydroxy” refers to the group -OH.
  • hydroxyalkyl by itself or as part of another substituent refers to an alkyl group in which one or more of the hydrogen atoms are replaced with a hydroxyl substituent.
  • hydroxyalkyl is meant to include monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, etc.
  • the alkyl can be a linear (i.e., straight or unbranched) or branched alkyl, accordingly, the “hydroxyalkyl” group includes linear hydroxyalkyl and branched hydroxyalkyl.
  • cyano or “-CN” refers to a group of -C ⁇ N.
  • cyanoalkyl or “-alk-CN” refers to an alkyl group having at least one -CN substituent.
  • the alkylene portion of the “-alk-CN” group is attached to the compound.
  • the alkyl can be a linear (i.e., straight or unbranched) or branched alkyl, accordingly, the “cyanoalkyl” group includes linear cyanoalkyl and branched cyanoalkyl.
  • alk- (alone or in combination with other terms) is an alkylene group, for example -alk-C (O) -R8.
  • haloalkoxy or “ (haloalkyl) oxy” refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • (haloalkyl) oxyalkyl refers to an alkyl group substituted with one, two, or three (haloalkyl) oxy groups.
  • absent that defines a variable, e.g., “X” , means that the defined variable is not present, and thus the two groups that connected through the variable are directly connected to each other.
  • bond refers to a covalent linkage between two atoms or two moieties, which may indicate a single bond, a double bond, or a triple bond.
  • stereoisomer refers to isomers of identical constitution that differ only in spatial arrangement of atoms, rather than order of atomic connectivity.
  • name or structure encompasses all possible stereoisomers, including essentially pure stereoisomers, as well as combination thereof.
  • Enantiomers and diastereomers are examples of stereoisomers.
  • enantiomer refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.
  • diastereomer refers to stereoisomers that are not mirror images.
  • racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
  • chiral refers to the structural characteristic of a molecule that makes it impossible to superimpose it on its mirror image.
  • tautomer refers to each of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an atom or group within the molecule. Thus, this disclosure is intended to cover all possible tautomer even when a structure depicts only one of them.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with the alkyl group.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethyl-aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methyl-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • a pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • a pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • a therapeutically effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
  • a therapeutically effective amount refers to that amount which has the effect of: (1) reducing the size of the tumor; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and/or (4) relieving one or more symptoms associated with the cancer.
  • the term “subject” or “patient” is used interchangeably and refers to any animal subject, including but not limited to human beings, laboratory animals (e.g., primates, rats, mice) , livestock (e.g., cows, sheep, goats, pigs, turkeys, and chickens) , and household pets (e.g., dogs, cats, and rodents) .
  • laboratory animals e.g., primates, rats, mice
  • livestock e.g., cows, sheep, goats, pigs, turkeys, and chickens
  • household pets e.g., dogs, cats, and rodents
  • the compounds taught herein can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the present teachings may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.
  • the present invention provides novel compounds of Formula (I) , or a pharmaceutically acceptable salt therefore, as IL-17A modulators.
  • certain compounds (or salts, prodrugs, or conjugates) of the present invention may exist in, and be isolated in, isomeric forms, including tautomeric forms, geometric isomers (i.e., cis-or trans-isomers) , optical isomers (i.e., enantiomers and diastereomers) , racemic forms, or any mixture of the isomeric forms described above.
  • the present invention encompasses a compound of Formula (I) in any of the isomeric forms or as a mixture thereof, for example, in the form of an active single enantiomer, racemic, or any mixture thereof.
  • the present invention is meant to comprehend all such isomeric forms of the compounds of Formula (I) .
  • the compound (or salt, prodrug or conjugate thereof) of the present invention may exhibit polymorphism or may form a solvent with water or an organic solvent.
  • the present invention also encompasses any such polymorphic form, any solvate or any mixture thereof.
  • Step 1 To a solution of 2-ethylpyrazole-3-carbaldehyde (230.0 mg, 1.9 mmol, 1.0 eq. ) and methyl (2S) -2-amino-2- (4-methylcyclohexyl) acetate (410.8 mg, 1.9 mmol, 1.0 eq., HCl salt) in toluene (30 mL) was added TEA (225.0 mg, 2.2 mmol, 1.2 eq. ) and MgSO4 (4.5 g, 37.1 mmol, 20.0 eq. ) . The mixture was stirred at 100 °C for 24 h. The reaction mixture was filtered, the filtrate was concentrated in vacuo.
  • Step 2 To a solution of methyl (2S) -2- [ (E) - (2-ethylpyrazol-3-yl) methyleneamino] -2- (4-methylcyclohexyl) acetate (500.0 mg, 1.7 mmol, 1.0 eq. ) and KHF2 (134.0 mg, 1.7 mmol, 56.6 ⁇ L, 1.0 eq. ) in CH3CN (6 mL) was added TFA (293.5 mg, 2.6 mmol, 191.2 ⁇ L, 1.5 eq. ) at 0 °C . After 5 mins, TMSCF3 (488.0 mg, 3.4 mmol, 2.0 eq. ) was added to the mixture.
  • reaction mixture was stirred at 25 °C for 1 h, another batch of TMSCF3 (488.0 mg, 2.0 eq. ) was added. the reaction mixture was stirred 25 °C for 1 h.
  • the reaction mixture was poured into water (10 ml) and neutralized with saturated NaHCO 3 , then extracted with EA (10 ml ⁇ 3) .
  • the combined organic phases were dried over Na 2 SO 4 , filtered.
  • the filtrate was concentrated in vacuo and purified by prep-HPLC (column: YMC-Actus Triart C18 150 ⁇ 30 mm ⁇ 5 ⁇ m; mobile phase: [water (0.1%TFA) -ACN] ; gradient: 52%-82%B over 11.5 min) .
  • Step 1 To a solution of 2-ethylpyrazole-3-carboxylic acid (100.0 mg, 713.6 ⁇ mol, 1.0 eq. ) in DMF (3 mL) was added HATU (407.0 mg, 1.1 mmol, 1.5 eq. ) and DIEA (276.7 mg, 2.1 mmol, 372.9 ⁇ L, 3.0 eq. ) at 20 °C. After 10 min, methyl (2S) -2-amino-2- (4-methylcyclohexyl) acetate (158.2 mg, 713.6 ⁇ mol, 1.0 eq., HCl salt) was added. The mixture was stirred at 20 °C for 16 h.
  • Step 2 To a solution of methyl (2S) -2- [ (2-ethylpyrazole-3-carbonyl) amino] -2- (4- methylcyclohexyl) acetate (198.0 mg, 644.1 ⁇ mol, 1.0 eq. ) in THF (3 mL) /H 2 O (1 mL) was added LiOH . H 2 O (54.1 mg, 1.3 mmol, 2.0 eq. ) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was poured into H 2 O (10 mL) and extracted with EtOAc (8 mL ⁇ 2) . The aqueous phase was adjusted to pH ⁇ 4.0 by 2 N HCl.
  • Step 1 To a solution of 4-nitro-2H-triazole (1.1 g, 9.6 mmol, 1.0 eq. ) in DMSO (20 mL) was added DIEA (3.7 g, 28.9 mmol, 5.0 mL, 3.0 eq. ) . Then ethyl 2-bromopropanoate (2.6 g, 14.5 mmol, 1.9 mL, 1.5 eq. ) was added. The mixture was stirred at 30 °C for 4 h. The mixture was poured into H 2 O (50 mL) and extracted with EtOAc (20 mL ⁇ 3) .
  • Step 1 To a solution of 2-hydrazinothioacetamide (4.0 g, 38.0 mmol, 1.0 eq. ) and ethyl 3-ethoxy-3-imino-propanoate hydrochloride (8.0 g, 40.9 mmol, 1.1 eq. ) in AcOH (8 mL) . The mixture was stirred at 55-120 °C for 1.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The precipitate was collected and crystallized from water to yield the product ethyl 2- (5-amino-1, 3, 4-thiadiazol-2-yl) acetate (4.5 g, 63.2%yield) was obtained as a white solid.
  • Step 2 To a solution of ethyl 2- (5-amino-1, 3, 4-thiadiazol-2-yl) acetate (4.0 g, 21.4 mmol, 1.0 eq. ) in DCM (40 mL) was added Boc 2 O (8.4 g, 38.5 mmol, 1.8 eq. ) and TEA (6.5 g, 64.1 mmol, 3.0 eq. ) and DMAP (261.0 mg, 2.1 mmol, 0.1 eq. ) . The mixture was stirred at 25 °C for 10 h. The mixture was poured into water (40 mL) and extracted with DCM (40 mL ⁇ 3) .
  • Step 3 To a solution of ethyl 2- [5- (tert-butoxycarbonylamino) -1, 3, 4-thiadiazol-2-yl] acetate (600.0 mg, 2.1 mmol, 1.0 eq. ) in THF (6 mL) was added LDA (2 M, 2.1 mL, 2.0 eq. ) at -78 °C. After the mixture was stirred at -78 °C, CH 3 I (311.2 mg, 2.2 mmol, 1.1 eq. ) was added. The mixture was stirred at -78 °C for 4 h. The mixture was poured into water (10 mL) and extracted with EA (10 mL ⁇ 3) .
  • Step 1 To a mixture of tert-butyl 2, 5-diazabicyclo [4.2.0] octane-2-carboxylate (0.3 g, 1.4 mmol, 1.0 eq. ) and formaldehyde (344.0 mg, 4.2 mmol, 3.0 eq. ) in MeOH (3 mL) was added NaBH 3 CN (177.6 mg, 2.8 mmol, 2.0 eq. ) in one portion at 0 °C under N 2 . The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water and extracted with EtOAc (10 mL ⁇ 3) .
  • Step 2 To a mixture of tert-butyl 5-methyl-2, 5-diazabicyclo [4.2.0] octane-2-carboxylate (0.5 g, 2.2 mmol, 1.0 eq. ) in DCM (2 mL) was added HCl/dioxane (2 M, 4 mL, 3.6 eq. ) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated. The residue was used into next step directly without further purification. Compound 2-methyl-2, 5-diazabicyclo [4.2.0] octane (350.0 mg, , 97.4%yield as HCl salt) as gray solid.
  • Step 1 To a solution of tert-butyl 4, 7-diazaspiro [2.5] octane-4-carboxylate (1.0 g, 4.7 mmol, 1.0 eq. ) in MeOH (10 mL) was added NaBH 3 CN (888.0 mg, 14.1 mmol, 3.0 eq. ) and formaldehyde (1.9 g, 23.6 mmol, 1.8 mL, 5.0 eq. ) . The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL ⁇ 2) . The combined organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated to afford the crude product which was used into the next step without further purification.
  • NaBH 3 CN 888.0 mg, 14.1 mmol, 3.0 eq.
  • formaldehyde 1.9 g, 23.6 mmol
  • Step 2 A mixture of tert-butyl 7-methyl-4, 7-diazaspiro [2.5] octane-4-carboxylate (1.0 g, 4.4 mmol, 1.0 eq. ) in HCl/dioxane (2 M, 22.1 mL, 10.0 eq. ) was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to afford the crude product which was used as HCl salt in the next step without further purification.
  • Step 3 A solution of tert-butyl N- [ (1R) -2- [4- (benzyloxycarbonylamino) -3-fluoro-phenyl] -1- (4-methylpiperazine-1-carbonyl) propyl] carbamate (1.0 g, 1.9 mmol, 1.0 eq. ) in 4 M HCl/dioxane (10 mL) was stirred at 25 °C for 2 h.
  • Step 4 To a solution of benzyl N- [4- [ (2R) -2-amino-1-methyl-3- (4-methylpiperazin-1-yl) -3-oxo-propyl] -2-fluoro-phenyl] carbamate (0.8 g, 1.9 mmol, 1.0 eq) . in DMF (10 mL) was added DIEA (0.3 g, 2.2 mmol, 1.2 eq. ) and propanoyl chloride (0.2 g, 2.24 mmol, 1.2 eq. ) . The mixture was stirred at 25 °C for 1 h under N 2 .
  • the reaction mixture was poured into H 2 O (100 mL) and extracted with EtOAc (40 mL ⁇ 3) .
  • the combined organic layers were washed with brine (80 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography ( 20 g Silica Flash Column, eluent of 0-10%ethyl acetate/MeOH @45 mL/min) .
  • Step 5 To a solution of benzyl N- [2-fluoro-4- [ (2R) -1-methyl-3- (4-methylpiperazin-1-yl) -3-oxo-2- (propanoylamino) propyl] phenyl] carbamate (800.0 mg, 1.7 mmol, 1.0 eq. ) in EtOH (8 mL) and THF (8 mL) was added Pd/C (351.4 mg, 330.2 ⁇ mol, 10%purity, 0.2 eq. ) . The mixture was stirred at 25 °C under H 2 (30 Psi) atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 6 To a solution of 6A (10.0 mg, 28.5 ⁇ mol, 1.0 eq. ) and (2S) -2- [ [1- (2-ethylpyrazol-3-yl) -2, 2, 2-trifluoro-ethyl] amino] -2- (4-methylcyclohexyl) acetic acid (9.9 mg, 28.5 ⁇ mol, 1.0 eq. ) in CH 3 CN (1 mL) was added TEA (8.7 mg, 85.6 ⁇ mol, 3.0 eq. ) and 2-chloro-1-methylpyridinium iodide (14.6 mg, 57.1 ⁇ mol, 2.0 eq. ) . The mixture was stirred at 50 °C for 2 h.
  • Step 1 To a solution of tert-butyl N- [ (1S) -2- [2-fluoro-4- [ (1S, 2R) -1-methyl-3- (4-methylpiperazin-1-yl) -3-oxo-2- (propanoylamino) propyl] anilino] -1- (4-methylcyclohexyl) -2-oxo-ethyl] carbamate (50.0 mg, 82.8 ⁇ mol, 1.0 eq. ) in DCM (0.5 mL) was added TFA (188.8 mg, 1.7 mmol, 20.0 eq. ) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product as colorless oil, which was used into next step without further purification.
  • Step 2 To a solution of N- [ (1R, 2S) -2- [4- [ [ (2S) -2-amino-2- (4-methylcyclohexyl) acetyl] amino] -3-fluoro-phenyl] -1- (4-methylpiperazine-1-carbonyl) propyl] propanamide (50.0 mg, 99.3 ⁇ mol, 1.0 eq. as TFA salt) in DMF (0.5 mL) was added TEA (30.1 mg, 297.8 ⁇ mol, 3.0 eq. ) and (4-nitrophenyl) N- (3, 3-difluorocyclobutyl) carbamate (81.0 mg, 297.8 ⁇ mol, 3.0 eq. ) .
  • Example 28 N- ( (2S) -1, 1-dicyclopropyl-3- ( (1- (1- (methyl (2, 2, 2-trifluoroethyl) amino) -1-oxopropan-2-yl) -1H-pyrazol-3-yl) amino) -3-oxopropan-2-yl) -1-ethyl-1H-pyrazole-5-carboxamide
  • Step 1 To a solution of ethyl 2-bromopropanoate (2.4 g, 13.3 mmol, 1.7 mL, 1.5 eq. ) and 3-nitro-1H-pyrazole (1.0 g, 8.8 mmol, 1.0 eq. ) in DMF (10 mL) was added K 2 CO 3 (3.7 g, 26.5 mmol, 3.0 eq. ) . The mixture was stirred at 25 °C for 2 hr. The reaction mixture was poured into H 2 O (35 mL) and extracted with EtOAc (40 mL ⁇ 3) .
  • Step 4 To a solution of N-methyl-2- (3-nitropyrazol-1-yl) -N- (2, 2, 2-trifluoroethyl) propanamide (300.0 mg, 1.1 mmol, 1.0 eq. ) in EtOAc (5 mL) and MeOH (5 mL) was added Pd/C (113.9 mg, 107.1 ⁇ mol, 10%purity, 0.1 eq. ) . The mixture was stirred at 30 °C for 4 h under H 2 (30 Psi) atmosphere. The mixture was filtered, and filtrate was concentrated under reduced pressure.
  • Step 5 To a solution of 2- (3-aminopyrazol-1-yl) -N-methyl-N- (2, 2, 2-trifluoroethyl) propanamide (220.0 mg, 879.2 ⁇ mol, 1.0 eq. ) and (2S) -2- (tert-butoxycarbonylamino) -3, 3-dicyclopropyl-propanoic acid (473.6 mg, 1.8 mmol, 2.0 eq. ) in pyridine (3 mL) was added EDCI (842.7 mg, 4.4 mmol, 5.0 eq. ) . The mixture was stirred at 25 °Cfor 2 h.
  • Step 6 A solution of tert-butyl N- [ (1S) -1- (dicyclopropylmethyl) -2- [ [1- [1-methyl-2- [methyl (2, 2, 2-trifluoroethyl) amino] -2-oxo-ethyl] pyrazol-3-yl] amino] -2-oxo-ethyl] carbamate (300.0 mg, 598.2 ⁇ mol, 1.0 eq. ) in HCl/dioxane (3 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 7 To a solution of 2-ethylpyrazole-3-carboxylic acid (32.0 mg, 228.4 ⁇ mol, 0.5 eq. ) and (2S) -2-amino-3, 3-dicyclopropyl-N- [1- [1-methyl-2- [methyl (2, 2, 2-trifluoroethyl) amino] -2-oxo-ethyl] pyrazol-3-yl] propanamide (200.0 mg, 456.7 ⁇ mol, 1.0 eq., HCl) in pyridine (4 mL) was added EDCI (350.2 mg, 1.8 mmol, 4.0 eq. ) . The mixture was stirred at 20 °C for 3 h.
  • Example 69 N- ( (1S) -2- ( (5- (cyclopropyl (2- (3, 3-difluorocyclobutyl) acetamido) methyl) thiazol-2-yl) amino) -1- (4, 4-difluorocyclohexyl) -2-oxoethyl) -1-ethyl-1H-pyrazole-5-carboxamide
  • Step 2 To a solution of tert-butyl N- [5- [ (tert-butylsulfinylamino) -cyclopropyl-methyl] thiazol-2-yl] carbamate (2.4 g, 6.4 mmol, 1.0 eq. ) in MeOH (50 mL) was added acetyl chloride (1.1 g, 14.1 mmol, 1.0 mL, 2.2 eq. ) at 0 °C. Then the mixture was stirred at 20 °C for 2 h. The reaction was adjusted to PH 7-8 with NH 3 ⁇ H 2 O. Then the reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 4 To a solution of tert-butyl N- [5- [benzyloxycarbonylamino (cyclopropyl) methyl] thiazol-2-yl] carbamate (1.3 g, 3.2 mmol, 1.0 eq. ) in ACN (10 mL) was added ZnBr2 (1.5 g, 6.4 mmol, 322.5 ⁇ L, 2.0 eq. ) . The mixture was stirred at 80 °C for 6 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water 30 mL and extracted with EtOAc 60 mL (20 mL ⁇ 3) .
  • Step 5 To a mixture of (2S) -2- (tert-butoxycarbonylamino) -2- (4, 4-difluorocyclohexyl) acetic acid (1.0 g, 3.4 mmol, 1.1 eq. ) and benzyl N- [ (2-aminothiazol-5-yl) -cyclopropyl-methyl] carbamate (1.2 g, 3.2 mmol, 1.0 eq. ) in pyridine (10 mL) was added EDCI (1.8 g, 9.5 mmol, 3.0 eq. ) . Then the mixture was stirred at 20 °C for 2 h.
  • Step 6 A solution of tert-butyl N- [ (1S) -2- [ [5- [benzyloxycarbonylamino (cyclopropyl) methyl] thiazol-2-yl] amino] -1- (4, 4-difluorocyclohexyl) -2-oxo-ethyl] carbamate (1.5 g, 2.6 mmol, 1.0 eq. ) in HCl/dioxane (10 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 8 To a solution of benzyl N- [cyclopropyl- [2- [ [ (2S) -2- (4, 4-difluorocyclohexyl) -2- [ (2-ethylpyrazole-3-carbonyl) amino] acetyl] amino] thiazol-5-yl] methyl] carbamate (1.0 g, 1.7 mmol, 1.0 eq. ) in THF (15 mL) was added TEA (690.7 mg, 6.8 mmol, 1.0 mL, 4.1 eq. ) , triethylsilane (800.8 mg, 6.9 mmol, 1.1 mL, 4.1 eq.
  • Step 9 To a solution of 2- (3, 3-difluorocyclobutyl) acetic acid (40.0 mg, 266.5 ⁇ mol, 1.1 eq.) and N- [ (1S) -2- [ [5- [amino (cyclopropyl) methyl] thiazol-2-yl] amino] -1- (4, 4-difluorocyclohexyl) -2-oxo-ethyl] -2-ethyl-pyrazole-3-carboxamide (220.0 mg, 235.8 ⁇ mol, 1.0 eq. ) in pyridine (2 mL) was added EDCI (136.0 mg, 709.4 ⁇ mol, 3.0 eq. ) .
  • Step 10 The residue was purified by SFC (column: Phenomenex-Cellulose-2 (250mm ⁇ 30mm, 10 um) ; mobile phase: [CO 2 -MeOH (0.1%NH 3 H 2 O) ] ; B%: 20%isocratic elution mode) .
  • Example 76 Methyl 4- (3, 3-difluoropyrrolidine-1-carbonyl) -4- (4- ( (S) -2- (1-ethyl-1H-pyrazole-5-carboxamido) -2- ( (1r, 4S) -4-methylcyclohexyl) acetamido) -1H-pyrazol-1-yl) piperidine-1-carboxylate
  • Step 1 To a mixture of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol, 1.0 eq. ) in THF (70 mL) was added NaH (2.7 g, 66.3 mmol, 60%purity, 1.5 eq. ) in one portion at 0°C under N 2 . The mixture was stirred at 25 °C for 30 min, then SEM-Cl (8.9 g, 53.1 mmol, 9.4 mL, 1.2 eq. ) was added and stirred for 2 h. The reaction mixture was poured into water (100 mL) . The aqueous layer was extracted with ethyl acetate (40 mL ⁇ 3) .
  • Step 3 To a mixture of 1- (2-trimethylsilylethoxymethyl) pyrazol-4-amine (0.6 g, 2.8 mmol, 1.0 eq. ) , (2S) -2- (tert-butoxycarbonylamino) -2- (4-methylcyclohexyl) acetic acid (763.1 mg, 2.8 mmol, 1.0 eq. ) and Pyridine (889.8 mg, 11.3 mmol, 908.0 ⁇ L, 4.0 eq. ) in DCM (30 mL) was added EDCI (1.1 g, 5.6 mmol, 2.0 eq. ) in one portion at 25°C under N 2 . The mixture was stirred at 25°Cfor 2 h.
  • Step 4 To a mixture of tert-butyl N- [ (1S) -1- (4-methylcyclohexyl) -2-oxo-2- [ [1- (2-trimethylsilylethoxymethyl) pyrazol-4-yl] amino] ethyl] carbamate (1.4 g, 3.0 mmol, 1.0 eq. ) in MeCN (12 mL) was added ZnBr 2 (1.9 g, 8.3 mmol, 414.8 ⁇ L, 2.8 eq. ) in one portion at 25°C under N 2 . The mixture was stirred at 80 °C for 6 h. The reaction mixture was poured into water (20 mL) .
  • Step 5 To a mixture of (2S) -2-amino-2- (4-methylcyclohexyl) -N- [1- (2-trimethylsilylethoxymethyl) pyrazol-4-yl] acetamide (1.1 g, 1.8 mmol, 1.0 eq. ) , 2-ethylpyrazole-3-carboxylic acid (246.0 mg, 1.8 mmol, 1.0 eq. ) and pyridine (833.1 mg, 10.5 mmol, 850.1 ⁇ L, 6.0 eq.) in DCM (20 mL) was added EDCI (673.0 mg, 3.5 mmol, 2.0 eq. ) in one portion at 25°C under N 2 .
  • Step 7 To a solution of 2-ethyl-N- [ (1S) -1- (4-methylcyclohexyl) -2-oxo-2- (1H-pyrazol-4-ylamino) ethyl] pyrazole-3-carboxamide (40.0 mg, 111.6 ⁇ mol, 1.0 eq. ) and tert-butyl 4-oxopiperidine-1-carboxylate (44.5 mg, 223.2 ⁇ mol, 2.0 eq. ) in THF (0.5 mL) was added NaOH (22.3 mg, 558.0 ⁇ mol, 5.0 eq. ) , then added chloroform (5.9 g, 49.6 mmol, 4.0 mL, 444.4 eq.
  • Step 8 To a solution of 1-tert-butoxycarbonyl-4- [4- [ [ (2S) -2- [ (2-ethylpyrazole-3-carbonyl) amino] -2- (4-methylcyclohexyl) acetyl] amino] pyrazol-1-yl] piperidine-4-carboxylic acid (30.0 mg, 51.2 ⁇ mol, 1.0 eq. ) and 3, 3-difluoropyrrolidine; hydrochloride (8.8 mg, 61.5 ⁇ mol, 1.2 eq. ) in DCM (0.3 mL) was added pyridine (32.4 mg, 410.0 ⁇ mol, 33.1 ⁇ L, 8.0 eq.
  • Step 9 A solution of tert-butyl 4- (3, 3-difluoropyrrolidine-1-carbonyl) -4- [4- [ [ (2S) -2- [ (2-ethylpyrazole-3-carbonyl) amino] -2- (4-methylcyclohexyl) acetyl] amino] pyrazol-1-yl] piperidine-1-carboxylate (30.0 mg, 44.5 ⁇ mol, 1.0 eq. ) in HCl/dioxane (4 M, 0.3 mL) was stirred at 25 °C for 1h.
  • Step 10 To a solution of N- [ (1S) -2- [ [1- [4- (3, 3-difluoropyrrolidine-1-carbonyl) -4-piperidyl] pyrazol-4-yl] amino] -1- (4-methylcyclohexyl) -2-oxo-ethyl] -2-ethyl-pyrazole-3-carboxamide (10.0 mg, 17.4 ⁇ mol, 1.0 eq. ) in DCM (0.1 mL) was added TEA (8.8 mg, 87.0 ⁇ mol, 12.1 ⁇ L, 5.0 eq. ) and methoxycarbonyl methyl carbonate (5.0 mg, 37.3 ⁇ mol, 4.0 ⁇ L, 2.0 eq.
  • Example B CXCL1 release assay in HT-29 cell
  • IL-17 signaling pathway by IL-17A inhibitors was evaluated by monitoring IL-17 induced CXCL1 production in the human colorectal adenocarcinoma epithelial HT-29 cell (ATCC, HTB-38) .
  • HT-29 cells were incubated in culture/assay medium (Mycos’ 5A + 10%FBS) .
  • Example C HEK-Blue assay for IL-17A/A inhibition assessment
  • Compound dilutions (3-fold serial dilution from 10000 to 1.52 nM) were mixed with 10ng/ml human IL-17A/A (Sino Biological #12047-HNAS) or IL-17A/F (Sino Biological #CT047-H08H) and transferred to 96-well assay plate at a volume of 50 ⁇ L. After a 30-min incubation, 50 ⁇ L of HEK-Blue IL-17 cells (3 x 10 4 cells) were added to each well and incubated for 20-24 hours at 37°Cwith 5%CO 2 . Following incubation, the supernatants were collected for SEAP analysis using Quanti-Blue solution (Invivogen #rep-qbs) . The data were processed and analyzed using Graphpad Prism10, and IC 50 values were determined using a four-parameter nonlinear fit.
  • Table 1 shows IC 50 values for IL-17A/A inhibition, IL-17 AA Hek-Blue, and CXCL1 Release of tested compounds. These compounds are categorized based on their IC 50 as follows: A: IC 50 ⁇ 100 nM; B: IC 50 between 100-1000 nM; and C: IC 50 > 1000 nM.

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Abstract

Entre autres, la présente invention concerne de nouveaux composés de formule (I) en tant qu'inhibiteurs de l'interleukine-17A (IL-17A), qui sont utiles pour le traitement d'états et de maladies médiés par IL-17A tels que des maladies inflammatoires.
PCT/CN2024/123669 2023-10-09 2024-10-09 Nouveaux inhibiteurs d'interleukine-17 Pending WO2025077732A1 (fr)

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CNPCT/CN2023/123488 2023-10-09
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CNPCT/CN2024/113080 2024-08-19
CN2024113080 2024-08-19
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020163554A1 (fr) * 2019-02-06 2020-08-13 Dice Alpha, Inc. Modulateurs d'il-17a et leurs utilisations
WO2021055376A1 (fr) * 2019-09-16 2021-03-25 Dice Alpha, Inc. Modulateurs d'il-17a et leurs utilisations
WO2021098844A1 (fr) * 2019-11-20 2021-05-27 成都先导药物开发股份有限公司 Immunomodulateur
WO2021239745A1 (fr) * 2020-05-27 2021-12-02 Sanofi Modulateurs de il-17a
WO2021239743A1 (fr) * 2020-05-27 2021-12-02 Sanofi Modulateurs de il-17a
WO2021250194A1 (fr) * 2020-06-12 2021-12-16 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023283453A1 (fr) * 2021-07-09 2023-01-12 Dice Alpha, Inc. Modulateurs d'il-17a à base de phényle acétamide et utilisations associées

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020163554A1 (fr) * 2019-02-06 2020-08-13 Dice Alpha, Inc. Modulateurs d'il-17a et leurs utilisations
WO2021055376A1 (fr) * 2019-09-16 2021-03-25 Dice Alpha, Inc. Modulateurs d'il-17a et leurs utilisations
WO2021098844A1 (fr) * 2019-11-20 2021-05-27 成都先导药物开发股份有限公司 Immunomodulateur
WO2021239745A1 (fr) * 2020-05-27 2021-12-02 Sanofi Modulateurs de il-17a
WO2021239743A1 (fr) * 2020-05-27 2021-12-02 Sanofi Modulateurs de il-17a
WO2021250194A1 (fr) * 2020-06-12 2021-12-16 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023283453A1 (fr) * 2021-07-09 2023-01-12 Dice Alpha, Inc. Modulateurs d'il-17a à base de phényle acétamide et utilisations associées

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