US 11,529,348 B2 · Pyrazolo[3,4-b]pyrazine derivatives as SHP2 phosphatase inhibitors

Abstract

Cellular biological activities are tightly controlled by intracellular signaling processes initiated by extracellular signals. Protein tyrosine phosphatases, which remove phosphate groups from tyrosine phosphorylated signaling molecules, play equally important tyrosine roles as protein kinases in signal transduction. SHP-2, a cytoplasmic SH2 domain containing protein tyrosine phosphatase, is involved in the signaling pathways of a variety of growth factors and cytokines. Recent studies have clearly demonstrated that this phosphatase plays an important role in transducing signal relay from the cell surface to the nucleus, and is a critical intracellular regulator in mediating cell proliferation and differentiation.

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Claims40

Dependent claims

A compound of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A is a 4-7 membered heterocyclyl, a monocyclic or bicyclic 6-10 membered aryl, a monocyclic 5-7 membered heteroaryl, or a bicyclic 8-10 membered heteroaryl, wherein the monocyclic 5-7 membered heteroaryl or the bicyclic 8-10 membered heteroaryl has 1 or more heteroatoms independently selected from the group consisting of N, O, and S, and further wherein A is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)R10, C(O)N(R10)2, N(R10)2, NR10C(O)R10, NR10S(O)wR10, OR10, ═O, OS(O)wR10, P(O)(R10)2, S(O)wR10, S(O)wN(R10)2, and R10;
X is a bond, —CRX2RX3—, —CRX4RX5NRX1—, —CRX4RX5O—, —CRX6═CRX7—, —C≡C—, —C(O)—, —C(O)NRX11—, —NRX1—, —NRX1CRX4RX5, —O—, —OCRX4RX5—, —S(O)w—, or cyclopropyl;
RX1 is H, C1-6 alkyl, or phenyl;
or
RX1 and A, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl, wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl optionally has 1 or more additional heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)R10, C(O)N(R10)2, N(R10)2, OR10, ═O, OS(O)wR10, P(O)(R10), S(O)wR10, S(O)wN(R10)2, and R10;
RX2 is H, halogen, C1-6 alkyl, C(O)NRaRb, NaRb, OH, or OC1-6 alkyl, wherein the C1-6 alkyl or OC1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX3 is H, halogen, C1-6 alkyl, C(O)NRaRb, NaRb, OH, or OC1-6 alkyl, wherein the C1-6 alkyl or OC1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
or
RX2 and RX3, together with the carbon atom to which they are attached, form a 3-6 membered carbocyclyl, wherein the 3-6 membered carbocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OC1-6 alkyl, and ═O;
RX4 is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX5 is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX6 is H, halogen, CN, C1-6 alkyl, or C(O)NRaRb, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX7 is H, halogen, CN, C1-6 alkyl, or C(O)NRaRb, wherein the C1-6 alkyl is optionally substituted by one or more independently selected RP substituents;
RX11 is H, C1-6 alkyl, or phenyl;
or
RX11 and A, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl, wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl optionally has 1 or more additional heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)R10, C(O)N(R10)2, N(R10)2, OR10, ═O, OS(O)wR10, P(O)(R10)2, S(O)wR10, S(O)wN(R10)2, S(O)NHR10, and R10;
each R10 is independently H, C1-6 alkyl, C2-6 heteroalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each C1-6 alkyl, C2-6 heteroalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C(NRa)Rb, C(O)R20, NaRb, OH, and OC1-6 alkyl;
each R20 is independently H, halogen, C1-6 alkyl, NRaRb, OH, or OC1-6 alkyl;
Y is —C1-3 alkylene-NRY—, —NRY—, or —NRY—C1-3 alkylene-;
RY is H, C1-6 alkyl, or phenyl;
B is a saturated 3-7 membered carbocyclyl or a saturated 4-7 membered heterocyclyl, wherein the saturated 4-7 membered heterocyclyl has 1 or 2 heteroatoms or heteroatomic groups independently selected from the group consisting of NRb, O, and S(O)w, and further wherein the saturated 3-7 membered carbocyclyl or the saturated 4-7 membered heterocyclyl is optionally substituted on one or more available carbons by one or more substituents independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)NRaRb, C(O)OH, C(O)OC1-6 alkyl, NRaRb, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, NRaS(O)2C1-6 alkyl, OH, OC1-6 alkyl, OC3-6 alkenyl, OC3-6 alkynyl, ═O, S(O)wC1-6 alkyl, S(O)2NRaRb, C3-6 cycloalkyl, C3-6 cycloalkoxy, aryl, and heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, NRaS(O)2C1-6 alkyl, OC1-6 alkyl, OC3-6 alkenyl, OC3-6 alkynyl, S(O)C1-6 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkoxy is optionally and independently substituted by one or more independently selected RP substituents, and further wherein each aryl and heteroaryl is optionally and independently substituted by one or more independently selected Rf substituents;
each Rf is independently RP, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, OC1-6 alkyl, S(O)wC1-6 alkyl, or C3-6 cycloalkyl, wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, NRaC(O)C1-6 alkyl, NRaC(O)OC1-6 alkyl, OC1-6 alkyl, S(O)wC1-6 alkyl, and C3-6 cycloalkyl is optionally and independently substituted by one or more independently selected RP substituents;
each Rh is independently H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C(O)C1-6 alkyl, C(O)NRaRb, C(O)OC1-6 alkyl, S(O)2C1-6 alkyl, S(O)2NRaRb, or C3-6 cycloalkyl, wherein each C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, S(O)2C1-6 alkyl, and C3-6 cycloalkyl is optionally and independently substituted by one or more independently selected RP substituents;
each RP is independently halogen, cyano, C(O)NRaRb, NaRb, NRaC(O)NRaRb, OH, OC1-6 alkyl, or SO2NRaRb;
Ra is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
Rb is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
or
Ra and Rb, together with the nitrogen atom to which they are attached, form a monocyclic 4-6 membered heterocyclyl, wherein the monocyclic 4-6 membered heterocyclyl optionally has an additional heteroatom selected from the group consisting of N, O, and S, and further wherein the monocyclic 4-6 membered heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
R3 is H, C1-6 alkyl, or phenyl;
and
each w is independently 0, 1, or 2.

30 more elements

A compound of Formula (III):

wherein:
A is a 4-7 membered heterocyclyl, phenyl, or a monocyclic 5-7 membered heteroaryl, wherein the monocyclic 5-7 membered heteroaryl has 1 or more heteroatoms independently selected from the group consisting of N, O, and S, and further wherein A is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)N(R10)2, N(R10)2, OR10, ═O, and R10;
X is a bond, —CRX2RX3—, —C(O)—, —NRX1—, —O—, or —S(O)w—;
RX1 is H, C1-6 alkyl, or phenyl;
or
RX1 and A, together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl, wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl optionally has 1 or more additional heteroatoms independently selected from the group consisting of N, O, and S, and further wherein the saturated or partially unsaturated 8-10 membered bicyclic heterocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, C(O)N(R10)2, N(R10)2, ═O, and R10;
RX2 is H, halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OH, or OC1-6 alkyl;
RX3 is H, halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OH, or OC1-6 alkyl;
or
RX2 and RX3, together with the carbon atom to which they are attached, form a 3-6 membered carbocyclyl, wherein the 3-6 membered carbocyclyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C(O)NRaRb, NRaRb, OC1-6 alkyl, and ═O;
each R10 is independently H, C1-6 alkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each C1-6 alkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, and C(O)R20;
each R20 is independently halogen, C1-6 alkyl, or OH;
RY is H, C1-6 alkyl, or phenyl;
R4 is H, halogen, cyano, C1-6 alkyl, C(O)NRaRb, or RaRb, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, NRaRb, OH, and ═O;
R5 is H, halogen, cyano, C1-6 alkyl, C(O)NRaRb, or RaRb, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, NRaRb, OH, and ═O;
T is —CH2—, —NRh—, —O—, or —S(O)w—;
each Rh is independently H, C1-6 alkyl, C(O)C1-6 alkyl, C(O)NRaRb, C(O)OC1-6 alkyl, S(O)2C1-6 alkyl, or S(O)2NRaRb, wherein each C1-6 alkyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, and S(O)2C1-6 alkyl is optionally and independently substituted by one or more substituents independently selected from the group consisting of halogen and OH;
Ra is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
Rb is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, OH, and ═O;
R3 is H, C1-6 alkyl, or phenyl;
m is 0, 1, or 2;
and
each w is independently 0, 1, or 2.

20 more elements

Dependencies are inferred from the claim text.

Description13,902 words

Summary1,658 words

#Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 contains two Src homology 2 (SH2) NH2-terminal domains and a C-terminal protein-tyrosine phosphatase domain. It is ubiquitously expressed in various tissues and cell types. SHP2 plays an important role in diverse signaling pathways to regulate cellular biological processes and is involved in the signaling pathways of a variety of growth factors and cytokines. Within a single signaling pathway, SHP2 can play both positive (signal enhancing) and negative (signal diminishing) roles in intracellular signaling processes. SHP2 is believed to function by dephosphorylating its associated signaling molecules, thereby attenuating the local signaling flow. However, the main effect of SHP2 action in most signaling pathways (e.g., growth factor, cytokine, and extracellular matrix receptors) is to enhance signal transduction. For example, SHP2 is a positive regulator of the ERK/MAPK signaling pathway, playing a key role in regulating cellular proliferation and survival. (For a review of SHP2 phosphatase, see, e.g, K. S. Grossman et al., Adv. Cancer Res. 2010, 106, 53-89; and references cited therein.)

#In the basal state, SHP2 is normally auto-inhibited due to intramolecular interactions between its N-terminal SH2 (N—SH2) domain and its catalytic (PTP) domain, which blocks access to the catalytic site. Activating proteins that interact with the SH2 domains induce a conformational change that reverses this inhibition and allows substrate access to the catalytic site. Mutations in the PTPN11 gene that affect the N—SH2 or PTP domain residues involved in basal inhibition of SHP2 result in more readily activatable forms of SHP2 protein, which can lead to unregulated or increased SHP2 activity. Such activated mutants of SHP2 have been associated with developmental disorders such as Noonan syndrome, where nearly all mutated forms of SHP2 demonstrate increased PTP activity. Thus, there is a need for SHP2 phosphatase inhibitor compounds and methods for treating cancer and other disorders with these compounds.

#It is understood that any of the embodiments described below can be combined in any desired way, and that any embodiment or combination of embodiments can be applied to each of the aspects described below, unless the context indicates otherwise.

Detailed description12,244 words

#Activating SHP2 mutations have been detected in juvenile myelomonocytic leukemia (e.g., Q506P), chronic myelomonocytic leukemia (e.g., Y63C), neuroblastoma (e.g., T507K), melanoma (e.g., R138Q), acute myeloid leukemia (e.g., G503V), breast cancer, lung cancer (e.g., E76V), colorectal cancer (e.g., E76G). (M. Bentires-Alj et al., in Cancer Res. 2004, 64, 8816-8820; and references cited therein.

#SHP2 phosphatase inhibitors are disclosed, e.g., in WO 2015/107493; WO 2015/107494; WO 2015/107495; and J. G. Fortanet et al., in J. Med. Chem. 2016, DOI: 10.1021/acs.jmedchem.6b00680; and references cited therein. The effects of SHP2 phsophatase inhibition are described, e.g., Y.-N. P. Chen et al., in Nature, 2016, doi:10.1038/nature18621; J. Wang et al., in J. Clin. Invest. 2016, 126, 2077-2092; and references cited therein.

#The compounds and/or compositions of the disclosure, alone or in combination with other treatments, may be effective in treating, reducing, and/or suppressing disorders related to SHP2 phosphatase activity such as, e.g., Noonan syndrome, Leopard Syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia, acute myeloid leukemia, HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer (including adenocarcinoma of the lung), colorectal cancer, esophageal cancer, gastric cancer, squamous-cell carcinoma of the head and neck (SCCHN), neutropenia (Kostmann's syndrome), and systemic lupus erythematosus. See, e.g, N. Aceto et al. Nature Medicine, 2012, 28, 529-538; C. M. Furcht et al. Oncogene, 2013, 32, 2346-2355; V. E. Schneeberger et al. Oncotarget, 2015, 6, 6191-6202; P. Cai et al., Biomedicine & Pharmacotherapy 2014, 68, 285-290; and references cited therein.

Pyrazolo[3,4-b]pyrazine derivatives as SHP2 phosphatase inhibitors

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Pyrazolo[3,4-b]pyrazine derivatives as SHP2 phosphatase inhibitors

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Abstract

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Claims40

Description13,902 words

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Life of this patent

Description13,902 words