AR095376A1 - 2-AZA-BICYCLE ACID [2.2.1] HEPTANO-3-CARBOXYLL (BENCIL-CIANO-METHYL) -CATPSIN C INHIBITING REPLACED AMIDS - Google Patents

2-AZA-BICYCLE ACID [2.2.1] HEPTANO-3-CARBOXYLL (BENCIL-CIANO-METHYL) -CATPSIN C INHIBITING REPLACED AMIDS

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Publication number
AR095376A1
AR095376A1 ARP140100916A ARP140100916A AR095376A1 AR 095376 A1 AR095376 A1 AR 095376A1 AR P140100916 A ARP140100916 A AR P140100916A AR P140100916 A ARP140100916 A AR P140100916A AR 095376 A1 AR095376 A1 AR 095376A1
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Argentina
Prior art keywords
alkylene
alkyl
ring
independently selected
haloalkyl
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ARP140100916A
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Spanish (es)
Inventor
Anderskewitz Ralf
Binder Florian
Grauert Matthias
Grundl Marc
Wilhelm Haebel Peter
Oost Thorsten
Pautsch Alexander
Peters Stefan
Vintonyak Viktor
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Boehringer Ingelheim Int
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Publication of AR095376A1 publication Critical patent/AR095376A1/en

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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Su uso como inhibidores de Catepsina C, composiciones farmacéuticas que contienen el mismo, y métodos para el uso del mismo como agentes para el tratamiento y/o la prevención de enfermedades conectadas con la actividad de dipeptidil peptidasa I, por ej. enfermedades respiratorias. Reivindicación 1: Un compuesto caracterizado porque tiene la fórmula (1) en donde R¹ se selecciona en forma independiente de H, alquil C₁₋₆, halógeno, HO-, alquil C₁₋₆-O-, H₂N-, alquil C₁₋₆-HN-, (alquil C₁₋₆)₂N- y alquil C₁₋₆-C(O)HN-; o dos R¹ son juntos alquileno C₁₋₄; R² se selecciona de R².¹; aril-, en forma opcional sustituido con uno, dos o tres residuos seleccionados en forma independiente de R².¹, en forma opcional sustituido con un R².³; heteroaril C₅₋₁₀, que contiene uno, dos, tres o cuatro heteroátomos seleccionados en forma independiente de S, S(O), S(O)₂, O y N, en donde los átomos de carbono del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².¹, en donde los átomos de nitrógeno del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².², en donde un átomo de carbono del anillo está sustituido en forma opcional con un R².³, un átomo de nitrógeno del anillo está sustituido en forma opcional con un R².⁴; y heterociclil C₅₋₁₀, que contiene uno, dos, tres o cuatro heteroátomos seleccionados en forma independiente de S, S(O), S(O)₂, O y N, en donde el anillo está total o parcialmente saturado, en donde los átomos de carbono del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos, tres o cuatro R².¹, en donde los átomos de nitrógeno del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².², en donde un átomo de carbono del anillo está sustituido en forma opcional con un R².³ o un R².⁵, un átomo de nitrógeno del anillo está sustituido en forma opcional con un R².⁴; o R² y R⁴ están juntos con dos átomos de carbono adyacentes del anillo de fenilo un arilo o heteroarilo de 5 ó 6 miembros, que contiene uno, dos o tres heteroátomos seleccionados en forma independiente de S, S(O), S(O)₂, O y N, en donde los átomos de carbono del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².¹, en donde los átomos de nitrógeno del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².²; R².¹ se selecciona en forma independiente de H, halógeno, NC-, O=, HO-, H-A-, H-A-alquileno C₁₋₆-, R².¹.¹-A-, alquil C₁₋₆-A-, cicloalquil C₃₋₈-A-, haloalquil C₁₋₆-A-, R².¹.¹-alquileno C₁₋₆-A-, alquil C₁₋₆-A-alquileno C₁₋₆-, cicloalquil C₃₋₈-A-alquileno C₁₋₆-, haloalquil C₁₋₆-A-alquileno C₁₋₆-, R².¹.¹-alquileno C₁₋₆-A-alquileno C₁₋₆-, R².¹.¹-A-alquileno C₁₋₆-, HO-alquileno C₁₋₆-A-, HO-alquileno C₁₋₆-A-alquileno C₁₋₆-, alquil C₁₋₆-O-alquileno C₁₋₆-A- y alquil C₁₋₆-O-alquileno C₁₋₆-A-alquileno C₁₋₆-; R².¹.¹ se selecciona en forma independiente de: aril-, en forma opcional sustituido en forma independiente entre sí con uno, dos o tres R².¹.¹.¹; heteroaril C₅₋₁₀, que contiene uno, dos, tres o cuatro heteroátomos seleccionados en forma independiente de S, S(O), S(O)₂, O y N, en donde los átomos de carbono del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².¹.¹.¹, en donde los átomos de nitrógeno del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².¹.¹.²; y heterociclil C₅₋₁₀, que contiene uno, dos, tres o cuatro heteroátomos seleccionados en forma independiente de S, S(O), S(O)₂, O y N, en donde el anillo está total o parcialmente saturado, en donde los átomos de carbono del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos, tres o cuatro R².¹.¹.¹, en donde los átomos de nitrógeno del anillo están sustituidos en forma opcional e independiente entre sí con uno, dos o tres R².¹.¹.²; R².¹.¹.¹ se selecciona en forma independiente de halógeno, HO-, O=, alquil C₁₋₆-, alquil C₁₋₆-O-, haloalquil C₁₋₆-, haloalquil C₁₋₆-O- y cicloalquil C₃₋₈-; R².¹.¹.² se selecciona en forma independiente de O=, alquil C₁₋₆-, haloalquil C₁₋₆-, cicloalquil C₃₋₈-, alquil C₁₋₆-O-alquil C₁₋₆, H(O)C-, alquil C₁₋₆-(O)C-, tetrahidrofuranilmetil- y tetrahidropiranilmetilo-; R².² se selecciona en forma independiente de H-A-alquileno C₁₋₆-, cicloalquil C₃₋₈-, alquil C₁₋₆-A-alquileno C₁₋₆-, cicloalquil C₃₋₈-A-alquileno C₁₋₆-, haloalquil C₁₋₆-A-alquileno C₁₋₆-, R².¹.¹-A-alquileno C₁₋₆-, alquil C₁₋₆-S(O)₂- y alquil C₁₋₆-C(O)-, R².¹.¹-A-; R².³ y R⁴ se seleccionan juntos de -O-, -S-, -N(R².³.¹)-, -C(O)N(R².³.¹)-, -N(R².³.¹)C(O)-, -S(O)₂N(R².³.¹)-, -N(R².³.¹)S(O)₂-, -C(O)O-, -OC(O)-, -C(O)-, -S(O)-, -S(O)₂-, R².³, R².³, -C(R².³.²)=C(R².³.²)-, -C=N-, -N=C-, -C(R².³.²)₂-O-, -O-C(R².³.²)₂-, -C(R².³.²)₂N(R².³.¹)-, y -N(R².³.¹)C(R².³.²)₂- y -alquileno C₁₋₄-; R².³.¹ se selecciona en forma independiente de H, alquil C₁₋₆, haloalquil C₁₋₆-, cicloalquil C₃₋₈-, HO-alquileno C₁₋₄-, (alquil C₁₋₄)-O-alquileno C₁₋₄-, H₂N-alquileno C₁₋₄-, (alquil C₁₋₄)HN-alquileno C₁₋₄- y (alquil C₁₋₄)₂N-alquileno C₁₋₄-; R².³.² se selecciona en forma independiente de H, alquil C₁₋₆-, haloalquil C₁₋₆-, cicloalquil C₃₋₈-, HO-alquileno C₁₋₄-, (alquil C₁₋₄)-O-alquileno C₁₋₄-, H₂N-alquileno C₁₋₄-, (alquil C₁₋₄)HN-alquileno C₁₋₄- y (alquil C₁₋₄)₂N-alquileno C₁₋₄-; R².⁴ y R⁴ se seleccionan juntos de -N(R².⁴.¹)-, -C(O)N(R².⁴.¹)-, -N(R².⁴.¹)C(O)-, -S(O)₂N(R².⁴.¹)-, -N(R².⁴.¹)S(O)₂-, -C(O)-, -S(O)-, -S(O)₂-, -C(R².⁴.²)=C(R².⁴.²)-, -C=N-, -N=C-, -C(R².⁴.²)₂N(R².⁴.¹)- y -N(R².⁴.¹)C(R².⁴.²)₂-, -alquileno C₁₋₄-; y R².⁴.¹ se selecciona en forma independiente de H, alquil C₁₋₆-, haloalquil C₁₋₆-, cicloalquil C₃₋₈-, HO-alquileno C₁₋₄-, (alquil C₁₋₄)-O-alquileno C₁₋₄-, H₂N-alquileno C₁₋₄-, (alquil C₁₋₄)HN-alquileno C₁₋₄- y (alquil C₁₋₄)₂N-alquileno C₁₋₄-; R².⁴.² se selecciona en forma independiente de H, -alquil C₁₋₆-, haloalquil C₁₋₆-, cicloalquil C₃₋₈-, HO-alquileno C₁₋₄-, (alquil C₁₋₄)-O-alquileno C₁₋₄-, H₂N-alquileno C₁₋₄-, (alquil C₁₋₄)HN-alquileno C₁₋₄- y (alquil C₁₋₄)₂N-alquileno C₁₋₄-; R².⁵ y R⁴ se seleccionan juntos de -C(R².⁵.¹)=, =C(R².⁵.¹)-, -N=; y R².⁵.¹ se selecciona en forma independiente de H, alquil C₁₋₆-, haloalquil C₁₋₆-, cicloalquil C₃₋₈-, HO-alquileno C₁₋₄-, (alquil C₁₋₄)-O-alquileno C₁₋₄-, H₂N-alquileno C₁₋₄-, (alquil C₁₋₄)HN-alquileno C₁₋₄- y (alquil C₁₋₄)₂N-alquileno C₁₋₄-; R³ es H o F; R⁴ se selecciona en forma independiente de F, Cl, fenil-H₂C-O-, HO-, alquil C₁₋₆-, haloalquil C₁₋₆-, cicloalquil C₃₋₈-, alquil C₁₋₆-O-, haloalquil C₁₋₆-O-, alquil C₁₋₆-HN-, (alquil C₁₋₆)₂-HN-, alquil C₁₋₆-HN-alquileno C₁₋₄- y (alquil C₁₋₆)₂-HN-alquileno C₁₋₄-; A es un enlace o se selecciona en forma independiente de -O-, -S-, -N(R⁵)-, -C(O)N(R⁵)-, -N(R⁵)C(O)-, -S(O)₂N(R⁵)-, -N(R⁵)S(O)₂-, -S(O)(=NR⁵)-N(R⁵)-, -N(R⁵)(NR⁵=)S(O)-, -S(=NR⁵)₂-N(R⁵)-,Its use as cathepsin C inhibitors, pharmaceutical compositions containing it, and methods for the use thereof as agents for the treatment and / or prevention of diseases connected with the activity of dipeptidyl peptidase I, e.g. respiratory diseases. Claim 1: A compound characterized in that it has the formula (1) wherein R¹ is independently selected from H, C₁₋₆ alkyl, halogen, HO-, C₁₋₆-O- alkyl, H₂N-, C₁₋₆- alkyl HN-, (C₁₋₆ alkyl) ₂N- and C₁₋₆-C (O) alkyl HN-; or two R¹ are together C₁₋₄ alkylene; R² is selected from R².¹; aril-, optionally substituted with one, two or three residues selected independently of R².¹, optionally substituted with an R².³; heteroaryl C₅₋₁₀, which contains one, two, three or four heteroatoms independently selected from S, S (O), S (O) ₂, O and N, where the ring carbon atoms are optionally substituted and independent of each other with one, two or three R².¹, where the nitrogen atoms of the ring are optionally substituted and independent of each other with one, two or three R².², where a carbon atom of the ring is optionally substituted with an R².³, a ring nitrogen atom is optionally substituted with an R².⁴; and heterocyclyl C₅₋₁₀, which contains one, two, three or four heteroatoms independently selected from S, S (O), S (O) ₂, O and N, where the ring is fully or partially saturated, where the carbon atoms of the ring are optionally and independently substituted with one, two, three or four R².¹, where the nitrogen atoms of the ring are optionally and independently substituted with one, two or three R².², where a carbon atom of the ring is optionally substituted with an R².³ or an R².⁵, a nitrogen atom of the ring is optionally substituted with an R².⁴; or R² and R⁴ are together with two adjacent carbon atoms of the phenyl ring a 5 or 6 membered aryl or heteroaryl, containing one, two or three heteroatoms independently selected from S, S (O), S (O) ₂, O and N, where the carbon atoms of the ring are optionally and independently substituted with one, two or three R².¹, where the ring nitrogen atoms are optionally and independently substituted with each other with one, two or three R².²; R².¹ is independently selected from H, halogen, NC-, O =, HO-, HA-, HA-C₁₋₆- alkylene, R².¹.¹-A-, C₁₋₆-A- alkyl, C₃₋₈-A- cycloalkyl, C₁₋₆-A- haloalkyl, R².¹.¹-C₁₋₆-A- alkylene, C₁₋₆-A-C₁₋₆-alkylene alkyl, C₃₋₈-A- cycloalkyl C₁₋₆- alkylene, C₁₋₆-A-C₁₋₆-alkylene alkyl, R².¹.¹-C₁₋₆-A-C₁₋₆-alkylene, R².¹.¹-A-C₁₋₆ alkylene -, HO-C₁₋₆-A- alkylene, HO-C₁₋₆-A-C₁₋₆-alkylene, C₁₋₆-O-C₁₋₆-A-alkyl and C₁₋₆-O-alkylene alkyl C₁₋₆-A-C₁₋₆-alkylene; R².¹.¹ is independently selected from: aril-, optionally substituted independently of one another with one, two or three R².¹.¹.¹; heteroaryl C₅₋₁₀, which contains one, two, three or four heteroatoms independently selected from S, S (O), S (O) ₂, O and N, where the ring carbon atoms are optionally substituted and independent of each other with one, two or three R².¹.¹.¹, where the ring nitrogen atoms are optionally substituted and independently of one another with one, two or three R².¹.¹.²; and heterocyclyl C₅₋₁₀, which contains one, two, three or four heteroatoms independently selected from S, S (O), S (O) ₂, O and N, where the ring is fully or partially saturated, where the carbon atoms of the ring are optionally and independently substituted with one, two, three or four R².¹.¹.¹, where the nitrogen atoms of the ring are optionally and independently substituted with one another , two or three R².¹.¹.²; R².¹.¹.¹ is independently selected from halogen, HO-, O =, C₁₋₆- alkyl, C₁₋₆-O- alkyl, C₁₋₆- haloalkyl, C₁₋₆-O- haloalkyl and cycloalkyl C₃₋₈-; R².¹.¹.² is independently selected from O =, C₁₋₆- alkyl, C₁₋₆- haloalkyl, C₃₋₈- cycloalkyl, C₁₋₆-O-C₁₋₆ alkyl, H (O) C-, C₁₋₆- (O) C- alkyl, tetrahydrofuranylmethyl- and tetrahydropyranylmethyl-; R².² is independently selected from HA-C₁₋₆- alkylene, C₃₋₈- cycloalkyl, C₁₋₆-A-C₁₋₆-alkyl, C₃₋₈-A-C₁₋₆-cycloalkyl, haloalkyl C₁₋₆-A-Cquile- alkylene, R².¹.¹-A-C₁₋₆- alkylene, C₁₋₆-S (O) ₂- alkyl and C₁₋₆-C (O) alkyl -, R² .¹.¹-A-; R².³ and R⁴ are selected together from -O-, -S-, -N (R².³.¹) -, -C (O) N (R².³.¹) -, -N (R².³. ¹) C (O) -, -S (O) ₂N (R².³.¹) -, -N (R².³.¹) S (O) ₂-, -C (O) O-, -OC ( O) -, -C (O) -, -S (O) -, -S (O) ₂-, R².³, R².³, -C (R².³.²) = C (R².³. ²) -, -C = N-, -N = C-, -C (R².³.²) ₂-O-, -OC (R².³.²) ₂-, -C (R².³.² ) ₂N (R².³.¹) -, and -N (R².³.¹) C (R².³.²) ₂- and -Cquile- alkylene; R².³.¹ is independently selected from H, C₁₋₆ alkyl, C₁₋₆- haloalkyl, C₃₋₈- cycloalkyl, HO-Cquile-alkylene, (C₁₋₄ alkyl) -O-C₁₋ alkylene ₄-, H₂N-C₁₋₄- alkylene, (C₁₋₄ alkyl) HN-C₁₋₄- alkylene and (C₁₋₄ alkyl) ₂N-C₁₋₄- alkylene; R².³.² is independently selected from H, C₁₋₆- alkyl, C₁₋₆- haloalkyl, C₃₋₈- cycloalkyl, HO-Cquile-alkylene, (C₁₋₄ alkyl) -O-C₁ alkylene ₋₄-, H₂N-C₁₋₄- alkylene, (C₁₋₄ alkyl) HN-C₁₋₄- alkylene and (C₁₋₄ alkyl) ₂N-C₁₋₄- alkylene; R².⁴ and R⁴ are selected together from -N (R².⁴.¹) -, -C (O) N (R².⁴.¹) -, -N (R².⁴.¹) C (O) -, -S (O) ₂N (R².⁴.¹) -, -N (R².⁴.¹) S (O) ₂-, -C (O) -, -S (O) -, -S (O) ₂-, -C (R².⁴.²) = C (R².⁴.²) -, -C = N-, -N = C-, -C (R².⁴.²) ₂N (R².⁴. ¹) - and -N (R².⁴.¹) C (R².⁴.²) ₂-, -Cquile alkylene; and R².⁴.¹ is independently selected from H, C₁₋₆- alkyl, C₁₋₆- haloalkyl, C₃₋₈- cycloalkyl, HO-Cquile-alkylene, (C₁₋₄ alkyl) -O-alkylene C₁₋₄-, H₂N-C₁₋₄- alkylene, (C₁₋₄ alkyl) HN-C₁₋₄- alkylene and (C₁₋₄ alkyl) ₂N-C₁₋₄- alkylene; R².⁴.² is independently selected from H, -C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₈ cycloalkyl, HO-Cquile-alkylene, (C₁₋₄ alkyl) -O-alkylene C₁₋₄-, H₂N-C₁₋₄- alkylene, (C₁₋₄ alkyl) HN-C₁₋₄- alkylene and (C₁₋₄ alkyl) ₂N-C₁₋₄- alkylene; R².⁵ and R⁴ are selected together from -C (R².⁵.¹) =, = C (R².⁵.¹) -, -N =; and R².⁵.¹ is independently selected from H, C₁₋₆- alkyl, C₁₋₆- haloalkyl, C₃₋₈- cycloalkyl, HO-Cquile-alkylene, (C₁₋₄ alkyl) -O-alkylene C₁₋₄-, H₂N-C₁₋₄- alkylene, (C₁₋₄ alkyl) HN-C₁₋₄- alkylene and (C₁₋₄ alkyl) ₂N-C₁₋₄- alkylene; R³ is H or F; R⁴ is independently selected from F, Cl, phenyl-H₂C-O-, HO-, C₁₋₆- alkyl, C₁₋₆- haloalkyl, C₃₋₈- cycloalkyl, C₁₋₆-O- alkyl, C₁₋ haloalkyl ₆-O-, C₁₋₆-HN- alkyl, (C₁₋₆ alkyl) ₂-HN-, C₁₋₆-HN-C₁₋₄ alkylene alkyl and (C₁₋₆ alkyl) ₂-HN-C₁₋ alkylene ₄-; A is a link or is independently selected from -O-, -S-, -N (R⁵) -, -C (O) N (R⁵) -, -N (R⁵) C (O) -, -S (O) ₂N (R⁵) -, -N (R⁵) S (O) ₂-, -S (O) (= NR⁵) -N (R⁵) -, -N (R⁵) (NR⁵ =) S (O) -, -S (= NR⁵) ₂-N (R⁵) -,

ARP140100916A 2013-03-14 2014-03-12 2-AZA-BICYCLE ACID [2.2.1] HEPTANO-3-CARBOXYLL (BENCIL-CIANO-METHYL) -CATPSIN C INHIBITING REPLACED AMIDS AR095376A1 (en)

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MA38473A1 (en) 2016-04-29

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