AR098290A1 - PIRIDAZINE DERIVATIVES AS RORg MODULATORS - Google Patents

PIRIDAZINE DERIVATIVES AS RORg MODULATORS

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AR098290A1
AR098290A1 ARP140104128A ARP140104128A AR098290A1 AR 098290 A1 AR098290 A1 AR 098290A1 AR P140104128 A ARP140104128 A AR P140104128A AR P140104128 A ARP140104128 A AR P140104128A AR 098290 A1 AR098290 A1 AR 098290A1
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Argentina
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alkyl
substituted
unsubstituted
alkoxy
haloalkyl
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ARP140104128A
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Spanish (es)
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Maxey Robert
Ward Stuart
Killen Jonathan
Bodil Van Niel Monique
Fauber Benjamin
Hurley Christopher
Cridland Andrew
Gobbi Alberto
Hurst David
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Hoffmann La Roche
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Abstract

Se divulgan métodos para producir los compuestos y usar los compuestos para el tratamiento de enfermedades inflamatorias, tales como artritis; donde RORg es un miembro huérfano de la subfamilia del receptor de hormona nuclear que incluye RORa y RORb; RORg controla la transcripción génica. Reivindicación 1: Un compuesto de fórmula (1), o una sal farmacéutica del mismo, en la que: X es: un enlace; -alquileno C₁₋₆; -NRᵃ-; -NRᵃ-alquileno C₁₋₆; -alquileno C₁₋₆-NRᵃ-; -O-; -O-alquileno C₁₋₆-; -alquileno C₁₋₆-O-; o -alquileno C₁₋₆-O-alquileno C₁₋₆; R¹ es hidrógeno; alquilo C₁₋₆; o -haloalquilo C₁₋₆; R² es hidrógeno; alquilo C₁₋₆; oxo; o -haloalquilo C₁₋₆; R³ es: hidrógeno; alquilo C₁₋₆; halo; hidroxi; alcoxi C₁₋₆; -O-C(O)-Rᵉ; -CN; carboxi; oxo; o =CH₂; en la que los restos alquilo C₁₋₆ pueden ser cada uno no sustituidos o sustituidos una o más veces con halo; o R² y R³ junto con los átomos a los que se unen pueden formar un doble enlace; R⁴ es: alquilo C₁₋₆; -haloalquilo C₁₋₆; halo; hidroxi; -hidroxialquilo C₁₋₆; alcoxi C₁₋₆-alquilo C₁₋₆; alcoxi C₁₋₆-alcoxi C₁₋₆-alquilo C₁₋₆; ciano, ciano-alquilo C₁₋₆; aminosulfonil-alquilo C₁₋₆; -(CRᶠRᵍ)ₘ-NRʰRⁱ; -(CRᶠRᵍ)ₘ-C(O)-NRʲRᵏ; -(CRᶠRᵍ)ₘ-C(O)-Rᵐ; -(CRᶠRᵍ)ₘ-NRᵖ-C(O)-Rⁿ; -(CRᶠRᵍ)ₘ-O-C(O)-Rⁿ; un heteroarilo de seis miembros seleccionado de piridazin-2-il, 1-metilpiridin-2-ona-6-il, piridin-2-il, y piridin-3-ilo, un heteroarilo de cinco miembros seleccionado de oxazolilo, isoxazolilo, oxadiazolilo, tiadiazolilo, imidazolilo, triazolilo y pirazolilo, cada uno de los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, alcoxi C₁₋₆, -hidroxialquilo C₁₋₆, alcoxi C₁₋₆-alquilo C₁₋₆, oxo, cicloalquilo C₃₋₆, -haloalquilo C₁₋₆, amino, N-alquilamino C₁₋₆, N,N-di-alquilamino C₁₋₆-alquilamino C₁₋₆, -cianoalquilo C₁₋₆, o alcoxicarbonilo C₁₋₆; heteroarilo-CH₂-, en la que el resto heteroarilo se selecciona de pirazolilo y oxadiazolilo, cada uno de los cuales puede estar no sustituido o sustituido una o mas veces con alquilo C₁₋₆, -hidroxialquilo C₁₋₆, -haloalquilo C₁₋₆, hidroxi, alcoxi C₁₋₆, alcoxi C₁₋₆-alquilo C₁₋₆, -aminoalquilo C₁₋₆, u oxo; heteroariloxi-CH₂-, en la que el resto heteroarilo se selecciona de oxadiazolilo, piridinilo, y pirazinilo, cada uno de los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, -hidroxialquilo C₁₋₆, -haloalquilo C₁₋₆, hidroxi, alcoxi C₁₋₆, alcoxi C₁₋₆-alquilo C₁₋₆, -aminoalquilo C₁₋₆, u oxo; fenil-alcoxi C₁₋₆-CH₂-, en la que el resto fenilo puede estar no sustituido o sustituido una o más veces con alcoxi C₁₋₆-carbonilo, carboxi, o aminocarbonilo; heterociclilo seleccionado de pirrolidinilo, imidazolidinilo, oxazolidinilo, y 1,1-dioxoisotiazolidinilo, cada uno de los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆ u oxo; o heterociclilo-CH₂-, en la que el resto heterociclilo se selecciona de imidazolidinilo, morfolin-4-il, y azetidinil cada uno do los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, oxo, mofoliniletil, o ciano; m es de 0 ó 2; R⁵ es alquilo C₁₋₆ que puede estar no sustituido o sustituido una o más veces por halo; R⁶ es alquilo C₁₋₆ que puede estar no sustituido o sustituido una o más veces con halo o alquilcarboniloxi C₁₋₆; o R⁵ y R⁶ junto con los átomos a los que están unidos pueden formar un anillo carbocíclico de tres a siete miembros que puede estar no sustituido o sustituido una o más veces con Rˣ, y en la que un átomo del anillo puede estar sustituido por un heteroátomo seleccionado de O, N y S; R⁷ es: hidrógeno; alquilo C₁₋₆; halo; o -haloalquilo C₁₋₆; Ar¹ es: arilo; o heteroarilo seleccionado de piridinilo, pirimidinilo, piridazinilo y tienilo; en la que el arilo y heteroarilo cada uno puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆ o halo; Rᵉ es: alquilo C₁₋₆; o alcoxi C₁₋₆,; cada uno de los cuales puede estar no sustituido o sustituido una o más veces con halo; Rᶠ y Rᵍ son cada uno independientemente: hidrógeno; o alquilo C₁₋₆; Rʰ es: hidrógeno; alquilo C₁₋₆; alcoxi C₁₋₆-alquilo C₁₋₆; -hidroxialquilo C₁₋₆; -aminoalquilo C₁₋₆; N-alquilamino C₁₋₆-alquilo C₁₋₆; N,N-di-alquilo C₁₋₆-amino-alquilo C₁₋₆; o -haloalquilo C₁₋₆; Rⁱ es: alquilo C₁₋₆; alcoxi C₁₋₆-alquilo C₁₋₆; -haloalquilo C₁₋₆; -hidroxialquilo C₁₋₆; alquilsulfonilo C₁₋₆; alquilcarbonilo C₁₋₆; hidroxialcoxi C₁₋₆; aminocarbonil-alquilo C₁₋₆, hidroxi-alquilo C₁₋₆-carbonilo, -cianoalquilo C₁₋₆; oxetanilo, alquilsulfonilo C₁₋₆; -haloalquilsulfonilo C₁₋₆; o heteroarilo seleccionado de oxadiazolilo, tiadiazolilo, piridinilo, pirimidinilo, y pirazinilo, cada uno de los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, -hidroxialquilo C₁₋₆, oxo, o -haloalquilo C₁₋₆; Rʲ es: hidrógeno; alquilo C₁₋₆; o bencilo; Rᵏ es: hidrógeno; alquilo C₁₋₆; -haloalquilo C₁₋₆; -cianoalquilo C₁₋₆; hidroxialcoxi C₁₋₆; alcoxi C₁₋₆; cicloalquilo C₃₋₆; cicloalquil C₃₋₆-alquilo C₁₋₆; heteroarilo seleccionado de oxadiazolilo, o piridinilo, cada uno do los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, ciano, alquilsulfonilo C₁₋₆, o halo; fenilo, el cual puede estar no sustituido o sustituido una o más veces con alquilsulfonilo C₁₋₆; o bencilo, la porción de fenilo del cual puede estar no sustituida o sustituida una o más veces con alquilo C₁₋₆, halo, o Rʲ y Rᵏ junto con los átomos a los que están unidos pueden formar un heterociclilo de cuatro a siete miembros seleccionado de: azetidinilo, morfolinilo, pirrolidinilo, azabiciclo[3.1.0]hexanilo, piperidinilo, piperazinilo, 2-oxa-5-azabiciclo[2.2.1]heptan-5-il, 3-azabiciclo[3.1.0]hexanilo, 2-azabiciclo[2.1.1]hexanilo, tetrahidro-1H-furo[3,4-c]pirrolilo, 2-oxa-6-azaespiro[3.4]octanilo, 5-oxa-2-azaespiro[3.4]octanilo, 2-azabiciclo[3.1.0]hexanilo, 2,5-diazabiciclo[2.2.1]heptanilo, 2-azaespiro[3.3]heptanilo, 7-azabiciclo[2.2.1]heptanilo, o 8-azabiciclo[3.2.1]octanilo, cada uno de los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, halo, amino, N-alquilamino C₁₋₆, N,N-di-alquilamino C₁₋₆, hidroxi, -alcoxicarbonilo C₁₋₆, alcoxi C₁₋₆, alquilsulfonilo C₁₋₆, -hidroxialquilo C₁₋₆, alcoxi C₁₋₆, -alquilo C₁₋₆, -haloalquilo C₁₋₆, ciano, -cianoalquilo C₁₋₆, aminocarbonilo, N-alquilamino C₁₋₆-carbonilo, N,N-di-alquilamino C₁₋₆-carbonilo, -alquilcarbonilamino C₁₋₆, -alcoxicarbonilamino C₁₋₆, alcoxicarbonilamino C₁₋₆-alquilo C₁₋₆, benciloxi, pirrolidinilo que pueden estar no sustituidos o sustituidos una o más veces con alquilo C₁₋₆ o halo; o heteroarilo seleccionado de pirazolilo, pirimidinilo, cada uno de los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, oxo o halo; Rᵐ es: hidrógeno; alquilo C₁₋₆; -cianoalquilo C₁₋₆; -haloalquilo C₁₋₆; -hidroxialquilo C₁₋₆; alcoxi C₁₋₆; cicloalquilo C₃₋₆; cicloalquil C₃₋₆-alquilo C₁₋₆; alcoxi C₁₋₆-alquilo C₁₋₆; -hidroxialquilo C₁₋₆; -aminoalquilo C₁₋₆; heteroarilo seleccionado de piridinilo, indolilo, e indolinilo; cada uno do los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, halo, ciano, -haloalquilo C₁₋₆, o alquilsulfonilo C₁₋₆; fenilo, el cual puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆; fenil-alquilo C₁₋₆; en el que la porción de fenilo del miso puede estar no sustituida o sustituida una o más veces con alquilo C₁₋₆, o heterociclilo seleccionado de azetidinilo, u oxetanilo, cada uno do los cuales puede estar no sustituido o sustituido una o más veces con alquilo C₁₋₆, halo, ciano, o -haloalquilo C₁₋₆; Rⁿ es: hidrógeno; alquilo C₁₋₆; -haloalquilo C₁₋₆; -hidroxialquilo C₁₋₆; hidroxialcoxi C₁₋₆; cicloalquilo C₃₋₆; cicloalquil C₃₋₆-alquilo C₁₋₆; alcoxi C₁₋₆, alcoxi C₁₋₆-alquilo C₁₋₆; -hidroxialquilo C₁₋₆, amino, N-alquilamino C₁₋₆, N,N-di-alquilamino C₁₋₆, -aminoalquilo C₁₋₆, N-alquilamino C₁₋₆-alquilo C₁₋₆, N,N-di-alquilamino C₁₋₆-alquilo C₁₋₆, aminocarbonil-alquilo C₁₋₆, N-alquilaminocarbonilo C₁₋₆; -alquilo C₁₋₆, N,N-di-alquilaminocarbonilo C₁₋₆-alquilo C₁₋₆, aminocarbonil-aminoalquilo C₁₋₆, 5-metilisoxazol-3-ilo; -cianoalquilo C₁₋₆; alquilsulfonilo C₁₋₆; alquilcarbonilamino C₁₋₆-alquilo C₁₋₆, o alquilsulfonil C₁₋₆-alquilo C₁₋₆; y Rᵖ es: hidrógeno; alquilo C₁₋₆; -haloalquilo C₁₋₆; -hidroxialquilo C₁₋₆; alcoxicarbonilo C₁₋₆-alquilo C₁₋₆; o -cianoalquilo C₁₋₆; siempre que cuando X es un enlace, R¹, R² y R³ son hidrógeno y R⁴ es alquilo C₁₋₆, y Ar¹ es 2,6-dihalofenilo.Methods for producing the compounds and using the compounds for the treatment of inflammatory diseases, such as arthritis, are disclosed; where RORg is an orphan member of the nuclear hormone receptor subfamily that includes RORa and RORb; RORg controls gene transcription. Claim 1: A compound of formula (1), or a pharmaceutical salt thereof, wherein: X is: a bond; -C₁₋₆ alkylene; -NRᵃ-; -NRᵃ-C₁₋₆ alkylene; -C₁₋₆-NRᵃ alkylene; -OR-; -O-C₁₋₆-alkylene; -C₁₋₆-O alkylene; or -C₁₋₆-O-C₁₋₆ alkylene; R¹ is hydrogen; C₁₋₆ alkyl; or -haloalkyl C₁₋₆; R² is hydrogen; C₁₋₆ alkyl; oxo; or -haloalkyl C₁₋₆; R³ is: hydrogen; C₁₋₆ alkyl; halo; hydroxy; C₁₋₆ alkoxy; -O-C (O) -Rᵉ; -CN; carboxy; oxo; o = CH₂; wherein the C₁₋₆ alkyl moieties may each be unsubstituted or substituted one or more times with halo; or R² and R³ together with the atoms to which they bind can form a double bond; R⁴ is: C₁₋₆ alkyl; -haloalkyl C₁₋₆; halo; hydroxy; -C₁₋₆ hydroxyalkyl; C₁₋₆-C₁₋₆-alkoxy; C₁₋₆-alkoxy-C₁₋₆-alkoxy-C₁₋₆ alkyl; cyano, cyano-C₁₋₆ alkyl; aminosulfonyl-C₁₋₆ alkyl; - (CRᶠRᵍ) ₘ-NRʰRⁱ; - (CRᶠRᵍ) ₘ-C (O) -NRʲRᵏ; - (CRᶠRᵍ) ₘ-C (O) -Rᵐ; - (CRᶠRᵍ) ₘ-NRᵖ-C (O) -Rⁿ; - (CRᶠRᵍ) ₘ-O-C (O) -Rⁿ; a six-membered heteroaryl selected from pyridazin-2-yl, 1-methylpyridin-2-one-6-yl, pyridin-2-yl, and pyridin-3-yl, a five-membered heteroaryl selected from oxazolyl, isoxazolyl, oxadiazolyl , thiadiazolyl, imidazolyl, triazolyl and pyrazolyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, C₁₋₆ alkoxy, -hydroxyalkyl C₁₋₆, C₁₋₆ alkoxy-C alquilo alkyl , oxo, C₃₋₆ cycloalkyl, C₁₋₆ -haloalkyl, amino, N-C₁₋₆ alkylamino, N, N-di-C₁₋₆-C₁₋₆ alkylamino, C₁₋₆ -cyanoalkyl, or C₁₋₆ alkoxycarbonyl ; heteroaryl-CH₂-, wherein the heteroaryl moiety is selected from pyrazolyl and oxadiazolyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, -hydroxyalkyl C₁₋₆, -haloalkyl C₁₋₆ , hydroxy, C₁₋₆ alkoxy, C₁₋₆-C₁₋₆-alkoxy, -C₁₋₆ -aminoalkyl, or oxo; heteroaryloxy-CH₂-, wherein the heteroaryl moiety is selected from oxadiazolyl, pyridinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, -hydroxyalkyl C₁₋₆, -haloalkyl C₁₋₆, hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C alquilo alkyl, -C₁₋₆ -aminoalkyl, or oxo; C₁₋₆-CH₂- phenyl-alkoxy, wherein the phenyl moiety may be unsubstituted or substituted one or more times with C₁₋₆-carbonyl, carboxy, or aminocarbonyl alkoxy; heterocyclyl selected from pyrrolidinyl, imidazolidinyl, oxazolidinyl, and 1,1-dioxoisothiazolidinyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl or oxo; or heterocyclyl-CH₂-, wherein the heterocyclyl moiety is selected from imidazolidinyl, morpholin-4-yl, and azetidinyl each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, oxo, mofolinylethyl, or cyano; m is 0 or 2; R⁵ is C₁₋₆ alkyl which may be unsubstituted or substituted one or more times by halo; R⁶ is C₁₋₆ alkyl which may be unsubstituted or substituted one or more times with halo or C₁₋₆ alkylcarbonyloxy; or R⁵ and R⁶ together with the atoms to which they are attached may form a three to seven membered carbocyclic ring that may be unsubstituted or substituted one or more times with Rˣ, and in which a ring atom may be substituted by a heteroatom selected from O, N and S; R⁷ is: hydrogen; C₁₋₆ alkyl; halo; or -haloalkyl C₁₋₆; Ar¹ is: aryl; or heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl and thienyl; wherein the aryl and heteroaryl each may be unsubstituted or substituted one or more times with C₁₋₆ alkyl or halo; Rᵉ is: C₁₋₆ alkyl; or C₁₋₆ alkoxy ;; each of which may be unsubstituted or substituted one or more times with halo; Rᶠ and Rᵍ are each independently: hydrogen; or C₁₋₆ alkyl; Rʰ is: hydrogen; C₁₋₆ alkyl; C₁₋₆-C₁₋₆-alkoxy; -C₁₋₆ hydroxyalkyl; -C₁₋₆ aminoalkyl; N-C₁₋₆-alkylamino-C₁₋₆ alkyl; N, N-di-C₁₋₆-alkyl-C₁₋₆-alkyl; or -haloalkyl C₁₋₆; Rⁱ is: C₁₋₆ alkyl; C₁₋₆-C₁₋₆-alkoxy; -haloalkyl C₁₋₆; -C₁₋₆ hydroxyalkyl; C₁₋₆ alkylsulfonyl; C₁₋₆ alkylcarbonyl; C₁₋₆ hydroxyalkoxy; aminocarbonyl-C₁₋₆ alkyl, hydroxy-C₁₋₆-alkylcarbonyl, -cyanoalkylC₁₋₆; oxetanyl, C₁₋₆ alkylsulfonyl; -haloalkylsulfonyl C₁₋₆; or heteroaryl selected from oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, -hydroxyalkyl C₁₋₆, oxo, or -haloalkyl C₁₋₆ ; Rʲ is: hydrogen; C₁₋₆ alkyl; or benzyl; Rᵏ is: hydrogen; C₁₋₆ alkyl; -haloalkyl C₁₋₆; -cyanoalkyl C₁₋₆; C₁₋₆ hydroxyalkoxy; C₁₋₆ alkoxy; C₃₋₆ cycloalkyl; C₃₋₆ cycloalkyl-C₁₋₆ alkyl; heteroaryl selected from oxadiazolyl, or pyridinyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, cyano, C₁₋₆ alkylsulfonyl, or halo; phenyl, which may be unsubstituted or substituted one or more times with C₁₋₆ alkylsulfonyl; or benzyl, the phenyl portion of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, halo, or Rʲ and Rᵏ together with the atoms to which they are attached may form a selected four to seven membered heterocyclyl from: azetidinyl, morpholinyl, pyrrolidinyl, azabicyclo [3.1.0] hexanyl, piperidinyl, piperazinyl, 2-oxa-5-azabicyclo [2.2.1] heptan-5-yl, 3-azabicyclo [3.1.0] hexanyl, 2- azabicyclo [2.1.1] hexanyl, tetrahydro-1H-furo [3,4-c] pyrrolyl, 2-oxa-6-azaspiro [3.4] octanyl, 5-oxa-2-azaspiro [3.4] octanyl, 2-azabicyclo [ 3.1.0] hexanyl, 2,5-diazabicyclo [2.2.1] heptanyl, 2-azaspiro [3.3] heptanyl, 7-azabicyclo [2.2.1] heptanyl, or 8-azabicyclo [3.2.1] octanyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, halo, amino, N-C₁₋₆ alkylamino, N, N-di-C₁₋₆ alkylamino, hydroxy, C₁₋₆ -alkoxycarbonyl, C₁ alkoxy ₋₆, C₁₋₆ alkylsulfonyl, -C₁₋₆ hydroxyalkyl, C alkoxy ₋₆, -C₁₋₆ alkyl, -C₁₋₆ -haloalkyl, cyano, -Cciano -alkyl alkyl, aminocarbonyl, N-C alqu-carbonyl alkylamino, N, N-di-C₁₋₆-carbonyl alkylamino, -C₁ alkylcarbonylamino ₋₆, -C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkoxycarbonylamino-C alquilo alkyl, benzyloxy, pyrrolidinyl which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl or halo; or heteroaryl selected from pyrazolyl, pyrimidinyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, oxo or halo; Rᵐ is: hydrogen; C₁₋₆ alkyl; -cyanoalkyl C₁₋₆; -haloalkyl C₁₋₆; -C₁₋₆ hydroxyalkyl; C₁₋₆ alkoxy; C₃₋₆ cycloalkyl; C₃₋₆ cycloalkyl-C₁₋₆ alkyl; C₁₋₆-C₁₋₆-alkoxy; -C₁₋₆ hydroxyalkyl; -C₁₋₆ aminoalkyl; heteroaryl selected from pyridinyl, indolyl, and indolinyl; each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, halo, cyano, C₁₋₆ -haloalkyl, or C₁₋₆ alkylsulfonyl; phenyl, which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl; phenyl-C₁₋₆ alkyl; wherein the phenyl portion of the miso may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, or heterocyclyl selected from azetidinyl, or oxetanyl, each of which may be unsubstituted or substituted one or more times with C₁₋₆ alkyl, halo, cyano, or Cha -haloalkyl; Rⁿ is: hydrogen; C₁₋₆ alkyl; -haloalkyl C₁₋₆; -C₁₋₆ hydroxyalkyl; C₁₋₆ hydroxyalkoxy; C₃₋₆ cycloalkyl; C₃₋₆ cycloalkyl-C₁₋₆ alkyl; C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆ alkyl; -C₁₋₆ hydroxyalkyl, amino, N-C₁₋₆-alkylamino, N, N-di-C₁₋₆ alkylamino, -C₁₋₆ -aminoalkyl, N-C₁₋₆-alkylamino-C₁₋₆-alkyl, N, N-di- C₁₋₆ alkylamino-C₁₋₆ alkyl, aminocarbonyl-C₁₋₆ alkyl, N-C-alkylaminocarbonyl; -C₁₋₆, N, N-di-C-alkylaminocarbonyl-C₁₋₆-alkyl, C-aminocarbonyl-aminoalkyl, 5-methylisoxazol-3-yl; -cyanoalkyl C₁₋₆; C₁₋₆ alkylsulfonyl; C₁₋₆-alkylcarbonylamino-C alquilo-alkyl, or Cils-alkylsulfonyl-C₁₋₆-alkyl; and Rᵖ is: hydrogen; C₁₋₆ alkyl; -haloalkyl C₁₋₆; -C₁₋₆ hydroxyalkyl; C₁₋₆ alkoxycarbonyl-C₁₋₆ alkyl; or -Cciano -alkyl alkyl; provided that when X is a bond, R¹, R² and R³ are hydrogen and R⁴ is C₁₋₆ alkyl, and Ar¹ is 2,6-dihalophenyl.

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